2-substituted benzimidazoles as selective androgen receptor modulators (SARMS)

ABSTRACT

The present invention is directed to a novel 2-substituted benzimidazole derivatives, pharmaceutical compositions containing them and their use in the treatment of disorders and conditions modulated by the androgen receptor.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.14/043,268, which claims priority to Ser. No. 13/050,578, filed Mar. 17,2011, issued as U.S. Pat. No. 8,575,206 and Ser. No. 11/626,030, filedJan. 23, 2007, issued as U.S. Pat. No. 7,932,399; which claims priorityfrom U.S. Provisional Application No. 60/761,548, filed Jan. 24, 2006,the entire disclosures of which are hereby incorporated in theirentirety.

FIELD OF THE INVENTION

The present invention is directed to novel 2-substituted benzimidazolederivatives, pharmaceutical compositions containing them and their usein the treatment of disorders and conditions modulated by the androgenreceptor. More particularly, the compounds of the present invention areuseful in the treatment of for example, prostate carcinoma, benignprostatic hyperplasia (BPH), hirsutism, alopecia, anorexia nervosa,breast cancer, acne, AIDS, cachexia, andropause, osteopenia,osteoporosis, female sexual dysfunction, male sexual dysfunction, as alibido enhancer, as a male contraceptive, as a male performance enhancerand/or for muscle replacement in burn recovery.

BACKGROUND OF THE INVENTION

Androgens are the anabolic steroid hormones of animals, controllingmuscle and skeletal mass, the maturation of the reproductive system, thedevelopment of secondary sexual characteristics and the maintenance offertility in the male. In women, testosterone is converted to estrogenin most target tissues, but androgens themselves may play a role innormal female physiology, for example, in the brain. The chief androgenfound in serum is testosterone, and this is the effective compound intissues such as the testes and pituitary. In prostate and skin,testosterone is converted to 5α-dihydrotestosterone (DHT) by the actionof 5α-reductase. DHT is a more potent androgen than testosterone becauseit binds more strongly to the androgen receptor.

Like all steroid hormones, androgens bind to a specific receptor insidethe cells of target tissues, in this case the androgen receptor. This isa member of the nuclear receptor transcription factor family. Binding ofandrogen to the receptor activates it and causes it to bind to DNAbinding sites adjacent to target genes. From there it interacts withcoactivator proteins and basic transcription factors to regulate theexpression of the gene. Thus, via its receptor, androgens cause changesin gene expression in cells. These changes ultimately have consequenceson the metabolic output, differentiation or proliferation of the cellthat are visible in the physiology of the target tissue.

Although modulators of androgen receptor function have been employedclinically for some time, both the steroidal (Basaria, S., Wahlstrom, J.T., Dobs, A. S., J. Clin Endocrinol Metab (2001), 86, pp 5108-5117;Shahidi, N. T., Clin Therapeutics, (2001), 23, pp 1355-1390), andnon-steroidal (Newling, D. W., Br. J. Urol., 1996, 77 (6), pp 776-784)compounds have significant liabilities related to their pharmacologicalparameters, including gynecomastia, breast tenderness andhepatotoxicity. In addition, drug-drug interactions have been observedin patients receiving anticoagulation therapy using coumarins. Finally,patients with aniline sensitivities could be compromised by themetabolites of non-steroidal antiandrogens.

Non-steroidal agonists and antagonists of the androgen receptor areuseful in the treatment of a variety of disorders and diseases. Moreparticularly, antagonists of the androgen receptor could be employed inthe treatment of prostate cancer, benign prostatic hyperplasia,hirsutism in women, alopecia, anorexia nervosa, breast cancer and acne.Agonists of the androgen receptor could be employed in malecontraception, male performance enhancement, as well as in the treatmentof cancer, AIDS, cachexia, and other disorders. Additionally, agonistsof the androgen receptor are useful in promoting burn recovery (Murphy,K. D., Suchmore, T., Micak, R. P., Chinkes, D. L., Klein, G. L.,Herndon, D. N., Effects of long-term oxandrolone administration inseverely burned children, Surgery, (2004), 136(2), pp 219-224).

Nonetheless, there exists a need for small molecule, non-steroidalantagonists of the androgen receptor. We now describe a novel series of2-substituted benzimidazole derivatives useful as androgen receptormodulators.

SUMMARY OF THE INVENTION

The present invention is directed to a compound of formula (I)

wherein

R¹ is selected from the group consisting of hydrogen, lower alkyl,—(CH₂)—(C₂₋₄ alkenyl), —(CH₂)—(C₂₋₄alkynyl), fluorinated lower alkyl,-(lower alkyl)-CN, —(CH₂)-heteroaryl, —(CH₂)-aryl, —SO₂-(lower alkyl),—SO₂-(phenyl), —SO₂-(tolyl), —(CH₂)-(fluorinated lower alkyl), -(loweralkyl)-C(O)—O-(lower alkyl), -(lower alkyl)-O-(lower alkyl), -(loweralkyl)-S(O)₀₋₂-(lower alkyl) and -(lower alkyl)-O—Si(CH₃)₂(t-butyl);

R² and R³ are each independently selected from the group consisting ofhalogen, hydroxy, carboxy, lower alkyl, halogen substituted lower alkyl,lower alkoxy, halogen substituted lower alkoxy, cyano, nitro, amino,lower alkylamino, di(lower alkyl)amino, —C(O)-(lower alkyl),—C(O)-(lower alkoxy), —C(O)—NR^(A)R^(B), —S(O)₀₋₂-(lower alkyl),—SO₂—NR^(A)R^(B), —N(R^(A))—C(O)-(lower alkyl) and—N(R^(A))—C(O)-(halogen substituted lower alkyl);

wherein each R^(A) and R^(B) is independently selected from hydrogen orlower alkyl;

R⁴ is selected from the group consisting of alkenyl, alkynyl, aryl,—(C₂₋₄alkyl)-aryl, heteroaryl and —(C₂₋₄alkyl)-heteroaryl;

wherein the alkenyl or alkynyl is optionally substituted with one ormore substituents independently selected from the group consisting ofhalogen, hydroxy, carboxy, cyano, nitro, NR^(E)R^(F), NR^(E)—C(O)-loweralkyl and phenyl; wherein R^(E) and R^(F) are each independentlyselected from hydrogen or lower alkyl; and wherein the phenyl(substituent on the alkenyl or alkynyl) is optionally substituted withone to four substituents independently selected from the groupconsisting of halogen, lower alkyl, lower alkoxy, hydroxy, carboxy,cyano, nitro, amino, (lower alkyl)amino and di(lower alkyl)amino;

wherein the aryl or heteroaryl, whether alone or as part of asubstituent group is optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, hydroxy, carboxy, lower alkyl, lower alkoxy, fluorinated loweralkyl, fluorinated lower alkoxy, phenoxy, cyano, nitro, NR^(C)R^(D) and-(lower alkyl)-NR^(B)R^(C), —C(O)-(lower alkyl), —C(O)-(lower alkoxy),—C(O)—NR^(C)R^(D), —N(R^(C))—C(O)-(lower alkyl), —N(R^(C))—C(O)-(halogensubstituted lower alkyl), —S(O)₀₋₂-(lower alkyl) and —SO₂—NR^(C)R^(D);wherein each R^(C) and R^(D) is independently selected from hydrogen orlower alkyl;

R⁵ is OR⁶; wherein R⁶ is selected from the group consisting of hydrogen,lower alkyl and —C(O)-(lower alkyl);

alternatively, R⁴ and R⁵ are taken together with the atom to which theyare bound to form a ring structure selected from the group consisting of2-pyrrolidinyl, 2-tetrahydro-furanyl, 2-(2,5-dihydro-1H-pyrrolyl),2-(2,5-dihydro-furanyl), 2-imidazolidinyl, 2-oxazolidinyl,2-[1,3]dioxolanyl, 2-piperidinyl, 6-(1,2,3,6-tetrahydro-pyridinyl),2-(1,2,3,6-tetrahydro-pyridinyl), 2-tetrahydropyranyl,6-(3,6-dihydro-2H-pyranyl), 2-(3,6-dihydro-2H-pyranyl),2-(hexahydro-pyrimidinyl), 2-[1,3]oxazinanyl and 2-[1,3]dioxanyl;

wherein the ring structure is optionally substituted with one or moresubstituents independently selected from the group consisting of loweralkyl, -(lower alkyl)-OH and -(lower alkyl)-(halogen);

and pharmaceutically acceptable salts thereof.

Illustrative of the invention is a pharmaceutical composition comprisinga pharmaceutically acceptable carrier and any of the compounds describedherein. An illustration of the invention is a pharmaceutical compositionmade by mixing any of the compounds described herein and apharmaceutically acceptable carrier. Illustrating the invention is aprocess for making a pharmaceutical composition comprising mixing any ofthe compounds described herein and a pharmaceutically acceptablecarrier.

Exemplifying the invention are methods of treating disorders andconditions modulated by the androgen receptor comprising administeringto a subject in need thereof, a therapeutically effective amount of anyof the compounds or pharmaceutical compositions described herein.

An example of the invention is a method of treating an androgen receptormodulated disorder selected from the group consisting of prostatecarcinoma, benign prostatic hyperplasia (BPH), hirsutism, alopecia,anorexia nervosa, breast cancer, acne, AIDS (Acquired Immune DeficiencySyndrome), cachexia, andropause, osteopenia, osteoporosis, female sexualdysfunction, male sexual dysfunction, diminished libido, malecontraception, or for enhanced male performance or for musclereplacement in burn recovery, comprising administering to a subject inneed thereof, a therapeutically effective amount of any of the compoundof pharmaceutical compositions described herein.

Another example of the invention is a method of treating an androgenreceptor modulated disorder selected from the group consisting prostatecarcinoma, BPH, hirsutism, alopecia, breast cancer, acne and malecontraception, comprising administering to a subject in need thereof, atherapeutically effective amount of any of the compound ofpharmaceutical compositions described herein.

Another example of the invention is a method of treating an androgenreceptor modulated disorder selected from the group consisting anorexia,AIDS, cachexia, andropause, osteopenia, osteoporosis, female sexualdysfunction, male sexual dysfunction, diminished libido, enhancing maleperformance, and muscle replacement in burn recovery, comprisingadministering to a subject in need thereof, a therapeutically effectiveamount of any of the compound of pharmaceutical compositions describedherein.

Another example of the invention is the use of any of the compoundsdescribed herein in the preparation of a medicament for treating: (a)prostate carcinoma, (b) benign prostatic hyperplasia (BPH), (c)hirsutism, (d) alopecia, (e) anorexia nervosa, (f) breast cancer, (g)acne, (h) AIDS, (i) cachexia, W andropause, (k) osteopenia, (l)osteoporosis, (m) female sexual dysfunction, (n) male sexualdysfunction, (o) diminished libido, for (p) male contraception, for (q)enhanced male performance or for (r) muscle replacement in burnrecovery, in a subject in need thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to a process for the preparation ofcompound of formula (I)

wherein R¹, R², R³, R⁴ and R⁵ are as herein defined. The compounds ofthe present invention are useful as selective androgen receptormodulators for the treatment of disorders mediated by at least oneandrogen receptor selected from the group consisting of prostatecarcinoma, benign prostatic hyperplasia (BPH), hirsutism, alopecia,anorexia nervosa, breast cancer, acne, AIDS, cachexia, andropause,osteopenia, osteoporosis, female sexual dysfunction, male sexualdysfunction and diminished libido, or for male contraception, forenhanced male performance or for muscle replacement in burn recovery.

Preferably, the disorder modulated by a least one androgen receptor isselected from the group consisting of cachexia, andropause,osteoperosis, osteopenia and muscle replacement in burn recovery, morepreferably, the disorder mediated by at least one androgen receptor isselected from the group consisting of cachexia, andropause, osteoperosisand osteopenia.

In an embodiment, the present invention is directed to compounds offormula (I) which are antagonists of an androgen receptor. In anotherembodiment, the present invention is directed to compounds of formula(I) which are agonists of an androgen receptor. In another embodiment,the present invention is directed to compounds of formula (I) whichexhibit tissue selective agonism and antagonism of an androgen receptor.

In an embodiment, the present invention is directed to compounds offormula (I) which are useful for the treatment of prostate cancer,benign prostatic hyperplasia, hirsutism in women, alopecia, anorexianervosa, breast cancer and acne. In another embodiment, the presentinvention is directed to compounds of formula (I) which are useful formale contraception, male performance enhancement, and/or for thetreatment of cancer, AIDS, cachexia, and/or for promoting musclereplacement in burn recovery.

In an embodiment of the present invention, R¹ is selected from the groupconsisting of hydrogen, lower alkyl, -(lower alkyl)-CN,—(CH₂)—(C₂₋₄alkenyl), —(CH₂)—(C₂₋₄alkynyl), fluorinated lower alkyl,—(CH₂)-heteroaryl, —(CH₂)-aryl, —(CH₂)-(fluorinated lower alkyl),-(lower alkyl)-C(O)—O-(lower alkyl), -(lower alkyl)-O-(lower alkyl), and-(lower alkyl)-O—Si(CH₃)₂(t-butyl).

In another embodiment of the present invention, R¹ is selected from thegroup consisting of hydrogen, lower alkyl, -(lower alkyl)-CN,—(CH₂)-heteroaryl, —(CH₂)—(C₂₋₄alkenyl), —(CH₂)—(C₂₋₄alkynyl), -(loweralkyl)-C(O)O-(lower alkyl) and -(lower alkyl)-O—Si(CH₃)₂(t-butyl). Inanother embodiment of the present invention, R¹ is selected from thegroup consisting of hydrogen, methyl, ethyl, cyano-methyl-,2-pyridyl-methyl-, allyl, 1-propyn-3-yl, methoxy-carbonyl-methyl- andt-butyl-dimethyl-silyloxy-ethyl-.

In another embodiment of the present invention, R¹ is selected from thegroup consisting of hydrogen, methyl, ethyl, cyano-methyl-,2-pyridyl-methyl-, allyl, 1-propyn-3-yl, methoxy-carbonyl-methyl- andt-butyl-dimethyl-silyloxy-ethyl-. In another embodiment of the presentinvention, R¹ is selected from the group consisting of hydrogen, ethyl,cyano-methyl-, allyl and 1-propyn-3-yl.

In another embodiment of the present invention, R¹ is selected from thegroup consisting of hydrogen and lower alkyl. In another embodiment ofthe present invention, R¹ is selected from the group consisting ofhydrogen and methyl. In another embodiment of the present invention, R¹is hydrogen.

In an embodiment of the present invention, R² and R³ are eachindependently selected from the group consisting of halogen, hydroxy,carboxy, lower alkyl, halogen substituted lower alkyl, cyano, nitro,amino, lower alkylamino, di(lower alkyl)amino, —C(O)-(lower alkyl),—C(O)-(lower alkoxy), —C(O)—NR^(A)R^(B), —N(R^(A))—C(O)-(lower alkyl)and —N(R^(A))—C(O)-(halogen substituted lower alkyl); wherein each R^(A)and R^(B) is independently selected from hydrogen methyl or ethyl.

In another embodiment of the present invention, R² and R³ are eachindependently selected from the group consisting of halogen, cyano andhalogen substituted lower alkyl. In another embodiment of the presentinvention, R² and R³ are each independently selected from the groupconsisting of chloro, trifluoromethyl and cyano. In another embodimentof the present invention, R² and R³ are each chloro;

In another embodiment of the present invention, R² and R³ are eachindependently selected from the group consisting of halogen and halogensubstituted lower alkyl. In another embodiment of the present invention,R² and R³ are each independently selected from the group consisting ofchloro and trifluoromethyl.

In an embodiment of the present invention, R² is selected from the groupconsisting of chloro and trifluoromethyl. In an embodiment of thepresent invention, R³ is selected from the group consisting of chloroand cyano. In another embodiment of the present invention, R³ is chloro;

In an embodiment of the present invention, R⁴ is selected from the groupconsisting of alkenyl, alkynyl, aryl, —(C₂₋₄alkyl)-aryl, heteroaryl and—(C₂₋₄alkyl)-heteroaryl; wherein the alkenyl or alkynyl is optionallysubstituted with one to two (preferably one) substituents independentlyselected from the group consisting of halogen, hydroxy, carboxy, cyano,nitro, NR^(E)R^(F), NR^(E)—C(O)-lower alkyl and phenyl; wherein R^(E)and R^(F) are each independently selected from hydrogen or lower alkyl;and wherein the phenyl is optionally substituted with one to two(preferably one) substituents independently selected from the groupconsisting of halogen, lower alkyl, lower alkoxy, hydroxy, carboxy,cyano, nitro, amino, (lower alkyl)amino and di(lower alkyl)amino; andwherein the aryl or heteroaryl, whether alone or as part of asubstituent group is optionally substituted with one to two substituents(preferably one) independently selected from the group consisting ofhalogen, hydroxy, carboxy, lower alkyl, lower alkoxy, fluorinated loweralkyl, fluorinated lower alkoxy, phenoxy, cyano, nitro, NR^(C)R^(D),-(lower alkyl)-NR^(B)R^(D), —C(O)-(lower alkyl) and —C(O)-(loweralkoxy); and wherein each R^(C) and R^(D) is independently selected fromhydrogen or lower alkyl. In another embodiment of the present invention,R⁴ is selected from the group consisting of alkenyl, alkynyl and aryl;wherein the aryl is optionally substituted as herein defined. In anotherembodiment of the present invention, R⁴ is selected from the groupconsisting of alkenyl and alkynyl.

In another embodiment of the present invention, R⁴ is selected from thegroup consisting of vinyl, (+)-vinyl, (−)-vinyl, allyl, (+)-allyl,(−)-allyl, 2-methyl-allyl, 2-propen-3-yl, Z-2-propen-3-yl,E-2-propen-3-yl, 3-methyl-1-propen-3-yl, 2-carboxy-1-propen-3-yl,3-phenyl-1-propen-3-yl, 3,3-dimethyl-1-propen-3-yl,2,3-dimethyl-2-propen-3-yl, 2-methyl-2-propen-3-yl), isopropenyl,propa-1,2-dien-3-yl, 3-methyl-propa-1,2-dien-3-yl,3-ethyl-propa-1,2-dien-3-yl), 1-buten-4-yl, 1-propyn-3-yl,(+)-1-propyn-3-yl, (−)-1-propyn-3-yl, 2-propyn-3-yl,1-hydroxy-2-propyn-3-yl, 1-phenyl-1-propyn-3-yl, 2-butyn-4-yl andphenyl.

In another embodiment of the present invention, R⁴ is selected from thegroup consisting of vinyl, allyl, (+)-allyl, (−)-allyl, 2-methyl-allyl,2-propen-3-yl, Z-2-propen-3-yl, E-2-propen-3-yl, 3-methyl-1-propen-3-yl,3-phenyl-1-propen-3-yl, 3,3-dimethyl-1-propen-3-yl,2,3-dimethyl-2-propen-3-yl, 2-methyl-2-propen-3-yl, isopropenyl,propa-1,2-dien-3-yl, 3-methyl-propa-1,2-dien-3-yl,3-ethyl-propa-1,2-dien-3-yl, 1-buten-4-yl, 1-propyn-3-yl,(+)-1-propyn-3-yl, (−)-1-propyn-3-yl, 2-propyn-3-yl and phenyl. Inanother embodiment of the present invention, R⁴ is selected from thegroup consisting of vinyl, (+)-vinyl, allyl, Z-2-propen-3-yl,propa-1,2-dien-3-yl, 1-propyn-3-yl, (+)-1-propyn-3-yl and(−)-1-propyn-3-yl. In another embodiment of the present invention, R⁴ isselected from the group consisting of isopropenyl, Z-2-propen-3-yl and(+)-vinyl.

In an embodiment of the present invention, R⁴ is selected from the groupconsisting of alkenyl, alkynyl and aryl; wherein the alkenyl isoptionally substituted with a substituent selected from the groupconsisting of hydroxy, carboxy and phenyl.

In another embodiment of the present invention, R⁴ is selected from thegroup consisting of vinyl, (+)-vinyl, (−)-vinyl, allyl, (+)-allyl,(−)-allyl, 2-methyl-allyl, 2-propen-3-yl, Z-2-propen-3-yl,E-2-propen-3-yl, 3-methyl-1-propen-3-yl, 2-carboxy-1-propen-3-yl,3-phenyl-1-propen-3-yl, 3,3-dimethyl-1-propen-3-yl,2,3-dimethyl-2-propen-3-yl, 2-methyl-2-propen-3-yl), isopropenyl,propa-1,2-dien-3-yl, 3-methyl-propa-1,2-dien-3-yl,3-ethyl-propa-1,2-dien-3-yl, 1-buten-4-yl, 1-propyn-3-yl, 2-propyn-3-yl,(+)-1-propyn-3-yl, (−)-1-propyn-3-yl, 1-hydroxy-2-propyn-3-yl,1-phenyl-1-propyn-3-yl, 2-butyn-4-yl and phenyl.

In another embodiment of the present invention, R⁴ is selected from thegroup consisting of isopropenyl, Z-2-propen-3-yl and (+)-vinyl.

In an embodiment of the present invention, R⁵ is OR⁶; wherein R⁶ isselected from the group consisting of hydrogen, methyl, ethyl,—C(O)-methyl and —C(O)-ethyl. In another embodiment of the presentinvention, R⁵ is OH.

In an embodiment of the present invention, R⁴ and R⁵ are taken togetherwith the atom to which they are bound to form a ring structure selectedfrom the group consisting of 2-pyrrolidinyl, 2-tetrahydro-furanyl,2-(2,5-dihydro-1H-pyrrolyl), 2-(2,5-dihydro-furanyl), 2-imidazolidinyl,2-oxazolidinyl, 2-[1,3]dioxolanyl, 2-piperidinyl,6-(1,2,3,6-tetrahydro-pyridinyl), 2-(1,2,3,6-tetrahydro-pyridinyl),2-tetrahydropyranyl, 6-(3,6-dihydro-2H-pyranyl),2-(3,6-dihydro-2H-pyranyl), 2-(hexahydro-pyrimidinyl), 2-[1,3]oxazinanyland 2-[1,3]dioxanyl; wherein the ring structure is optionallysubstituted with one or more substituents (preferably one to two, morepreferably one substituent) independently selected from the groupconsisting of C₁₋₂alkyl, —(C₁₋₂alkyl)-OH and —(C₁₋₂alkyl)-halogen.

In another embodiment of the present invention, R⁴ and R⁵ are takentogether with the atom to which they are bound to form a ring structureselected from the group consisting of 2,5-dihydro-furanyl,2-tetrahydrofuranyl, 2-[1,3]-dioxolanyl, 2-[1,3]dioxanyl, 2-imidazolyland 2-oxazolidinyl; wherein the ring structure is optionally substitutedwith one or more substituents (preferably one to two, more preferablyone substituent) independently selected from the group consisting ofmethyl, ethyl, hydroxymethyl, hydroxyethyl, and —(C₁₋₂alkyl)-halogen.

In another embodiment of the present invention, R⁴ and R⁵ are takentogether with the atom to which they are bound to form a ring structureselected from the group consisting of 2,5-dihydro-furanyl,2-tetrahydrofuranyl, 2-[1,3]-dioxolanyl,2-(4-hydroxymethyl-[1,3]dioxalanyl), 2-(4-chloromethyl-[1,3]dioxalanyl,2-[1,3]dioxanyl, 2-imidazolyl and 2-oxazolidinyl.

In another embodiment of the present invention, R⁴ and R⁵ are takentogether with the atom to which they are bound to form a ring structureselected from the group consisting of 2-tetrahydrofuranyl,2-[1,3]-dioxolanyl, 2-(4-hydroxymethyl-[1,3]dioxalanyl),2-(4-chloromethyl-[1,3]dioxalanyl, 2-[1,3]dioxanyl, 2-imidazolyl and2-oxazolidinyl.

In another embodiment of the present invention, R⁴ and R⁵ are takentogether with the atom to which they are bound to form a ring structureselected from the group consisting of 2,5-dihydro-furanyl and2-tetrahydrofuranyl. In another embodiment of the present invention, R⁴and R⁵ are taken together with the atom to which they are bound to form2-[1,3]dioxalanyl.

Additional embodiments of the present invention, include those whereinthe substituents selected for one or more of the variables definedherein (i.e. R¹, R², R³, R⁴, R⁵, R⁶) are independently selected to beany individual substituent or any subset of substituents selected fromthe complete list as defined herein.

Additional embodiments of the present invention include any singlecompound or subset of compounds selected from the representativecompounds listed in Tables 1-2 below.

Representative compounds of the present invention are as listed in Table1 to 2 below. Unless otherwise noted, wherein a stereogenic center ispresent in the listed compound, the compound was prepared as a mixtureof stereo-configurations. Where a stereogenic center is present, the(+)- and (−)-designations are intended to indicate that the exactstereo-configuration of the center has not been determined, but thedirection of the optical rotation has been determined.

TABLE 1 Representative Compounds of Formula (I)

ID No. R¹ R² R³ R⁴ 1 H chloro chloro allyl 2 H chloro chloro1-propyn-3-yl 3 H chloro chloro propa-1,2-dien-3-yl 4 H chloro chlorovinyl 6 H chloro chloro 3-methyl-propa-1,2-dien-3-yl 8 H chloro chloro2-propyn-3-yl 9 H chloro chloro isopropenyl 10 H chloro chloro phenyl 13H chloro chloro 2-methyl-allyl 14 H chloro chloro 2-methyl-2-propen-3-yl15 H chloro chloro Z-2-propen-3-yl 16 H chloro chloro E-2-propen-3-yl 17H chloro chloro 1-hydroxy-2-propyn-3-yl 23 H chloro chloro (+30)-allyl24 H chloro chloro (-)-allyl 25 H chloro chloro3,3-dimethyl-1-propen-3-yl 26 H chloro chloro 3-methyl-1-propen-3-yl 27H chloro chloro 2-carboxy-1-propen-3-yl 28 H chloro chloro3-phenyl-1-propen-3-yl 31 H chloro chloro -1-propyn-3-yl 32 H chlorochloro (−)-1-propyn-3-yl 33 H chloro chloro 2-butyn-1-yl 34 H chlorochloro 1--phenyl-1-propyn-3-yl 35 methyl chloro chloro 1-propyn-3-yl 36methyl chloro chloro (+)-1-propyn-3-yl 37 methyl chloro chloro(−)-1-propyn-3-yl 38 H trifluoro- cyano allyl methyl 39 H trifluoro-cyano 1-propyn-3-yl methyl 40 H chloro chloro 1-buten-4-yl 41 Htrifluoro- cyano 3-methyl-propa-1,2-dien3-yl methyl 42 H chloro chloro2,3-dimethyl-2-propen-3-yl 43 H chloro chloro (+)-vinyl 44 H chlorochloro (−)-vinyl 62 H chloro chloro 3-ethyl-propa-1,2-dien-3-yl

TABLE 2 Representative Compounds of Formula (I)

No. R¹ R² R³

45 H chloro chloro 2,5-dihydro-furanyl 46 H chloro chloro2-tetrahydro-furanyl 47 H chloro chloro 2-[1,3]dioxolanyl 482-pyridyl-methyl- chloro chloro 2-[1,3]dioxolanyl 49 H chloro chloro2-(4-hydroxymethyl- [1,3]dioxalanyl) 50 H chloro chloro2-(4-chloromethyl- [1,3]dioxalanyl) 51 H chloro chloro 2-[1,3]dioxanyl52 methyl chloro chloro 2-(4-hydroxymethyl- [1,3]dioxalanyl) 53cyano-methyl- chloro chloro 2-(4-chloromethyl- [1,3]dioxalanyl) 541-propyn-3-yl chloro chloro 2-[1,3]dioxolanyl 55 allyl chloro chloro2-[1,3]dioxolanyl 56 ethyl chloro chloro 2-[1,3]dioxolanyl 57methoxy-carbonyl- chloro chloro 2-[1,3]dioxolanyl methyl- 58t-butyl-dimethyl- chloro chloro 2-[1,3]dioxolanyl silyloxy-ethyl- 59 Htrifluoro- cyano 2-[1,3]dioxolanyl methyl 60 H chloro chloro2-imidazolidinyl 61 H chloro chloro 2-oxazolidinyl

As used herein, “halogen” shall mean chlorine, bromine, fluorine andiodine.

As used herein, the term “alkyl” whether used alone or as part of asubstituent group, include straight and branched chains. For example,alkyl radicals include methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, t-butyl, pentyl and the like. Unless otherwisenoted, “lower” when used with alkyl means a carbon chain composition of1-4 carbon atoms.

As used herein, the term “alkenyl” whether used alone or as part of asubstituent group, include straight and branched carbon chains, whereinthe carbon chain contains at least one, preferably one to two, morepreferably one double bond. For example, alkenyl radicals include, butare not limited to allyl, 1-propen-3-yl, 1-buten-4-yl,propa-1,2-dien-3-yl, and the like. Unless otherwise noted, “lower” whenused with alkenyl means a carbon chain composition of 2-4 carbon atoms.

As used herein, the term “alkynyl” whether used alone or as part of asubstituent group, include straight and branched carbon chains, whereinthe carbon chain contains at least one, preferably one to two, morepreferably one triple bond. For example, alkynyl radicals include, butare not limited to vinyl, 1-propyn-3-yl, 2-butyn-4-yl, and the like.Unless otherwise noted, “lower” when used with alkynyl means a carbonchain composition of 2-4 carbon atoms.

As used herein, unless otherwise noted, the term “halogen substitutedalkyl” or “halogen substituted lower alkyl” shall mean any alkyl orlower alkyl group as defined above substituted with a least one halogenatom selected from the group consisting of F, Cl, Br or I, preferably F,Cl or Br, more preferably F or Cl, most preferably F. Similarly, as usedherein, unless otherwise noted, the term “fluorinated alkyl” or“fluorinated lower alkyl” shall mean any alkyl or lower alkyl group asdefined above substituted with a least one fluoro atom. Suitableexamples include but are not limited to —CF₃, —CH₂—CF₃,—CF₂—CF₂—CF₂—CF₃, and the like. Preferably, the fluorinated alkyl orfluorinated lower alkyl is —CF₃.

As used herein, unless otherwise noted, “alkoxy” shall denote an oxygenether radical of the above described straight or branched chain alkylgroups. For example, methoxy, ethoxy, n-propoxy, sec-butoxy, t-butoxy,n-hexyloxy and the like.

As used herein, unless otherwise noted, the term “halogen substitutedalkoxy” or “halogen substituted lower alkoxy” shall mean any alkoxy orlower alkoxy group as defined above substituted with a least one halogenatom selected from the group consisting of F, Cl, Br or I, preferably F,Cl or Br, more preferably F or Cl, most preferably F. Similarly, as usedherein, unless otherwise noted, the term “fluorinated alkoxy” or“fluorinated lower alkoxy” shall mean any alkoxy or lower alkoxy groupas defined above substituted with a least one fluoro atom. Suitableexamples include but are not limited to —OCF₃, —OCH₂—CF₃,—OCF₂—CF₂—CF₂—CF₃, and the like. Preferably, the fluorinated alkoxy orfluorinated lower alkoxy is —OCF₃.

As used herein, unless otherwise noted, “aryl” shall refer tounsubstituted carbocylic aromatic groups such as phenyl, naphthyl, andthe like.

As used herein, unless otherwise noted, “heteroaryl” shall denote anyfive or six membered monocyclic aromatic ring structure containing atleast one heteroatom selected from the group consisting of O, N and S,optionally containing one to three additional heteroatoms independentlyselected from the group consisting of O, N and S; or a nine or tenmembered bicyclic aromatic ring structure containing at least oneheteroatom selected from the group consisting of O, N and S, optionallycontaining one to four additional heteroatoms independently selectedfrom the group consisting of O, N and S. The heteroaryl group may beattached at any heteroatom or carbon atom of the ring such that theresult is a stable structure.

Examples of suitable heteroaryl groups include, but are not limited to,pyrrolyl, furyl, thienyl, oxazolyl, imidazolyl, purazolyl, isoxazolyl,isothiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, pyranyl, furazanyl, indolizinyl, indolyl,isoindolinyl, indazolyl, benzofuryl, benzothienyl, benzimidazolyl,benzthiazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl,isothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl,naphthyridinyl, pteridinyl, and the like.

As used herein, the notation “*” shall denote the presence of astereogenic center.

When a particular group is “substituted” (e.g., alkenyl, aryl,heteroaryl, etc), that group may have one or more substituents,preferably from one to five substituents, more preferably from one tothree substituents, most preferably from one to two substituents,independently selected from the list of substituents.

With reference to substituents, the term “independently” means that whenmore than one of such substituents is possible, such substituents may bethe same or different from each other.

To provide a more concise description, some of the quantitativeexpressions given herein are not qualified with the term “about”. It isunderstood that whether the term “about” is used explicitly or not,every quantity given herein is meant to refer to the actual given value,and it is also meant to refer to the approximation to such given valuethat would reasonably be inferred based on the ordinary skill in theart, including approximations due to the experimental and/or measurementconditions for such given value.

As used herein, unless otherwise noted, the term “nitrogen protectinggroup” shall mean a group which may be attached to a nitrogen atom toprotect said nitrogen atom from participating in a reaction and whichmay be readily removed following the reaction. Suitable nitrogenprotecting groups include, but are not limited to carbamates—groups ofthe formula —C(O)O—R wherein R is for example methyl, ethyl, t-butyl,benzyl, phenylethyl, CH₂═CH—CH₂—, and the like; amides—groups of theformula —C(O)—R′ wherein R′ is for example methyl, phenyl,trifluoromethyl, and the like; N-sulfonyl derivatives—groups of theformula —SO₂—R″ wherein R″ is for example tolyl, phenyl,trifluoromethyl, 2,2,5,7,8-pentamethylchroman-6-yl-,2,3,6-trimethyl-4-methoxybenzene, and the like. Other suitable nitrogenprotecting groups may be found in texts such as T. W. Greene & P. G. M.Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.

Under standard nomenclature used throughout this disclosure, theterminal portion of the designated side chain is described first,followed by the adjacent functionality toward the point of attachment.Thus, for example, a “phenyl-(C₁-C₆alkyl)-aminocarbonyl-(C₁-C₆alkyl)”substituent refers to a group of the formula

Abbreviations used in the specification, particularly the Schemes andExamples, are as follows:

AIDS=Acquired Immune Deficiency Syndrome

AR=Androgen Receptor

BPH=Benign Prostatic Hyperplasia

n-BuLi=n-Butyl Lithium

DCM=Dichloromethane

DHT=5α-Dihydrotestosterone

DMF=N,N-Dimethylformamide

DMSO=Dimethylsulfoxide

Et₂O=Diethyl ether

EtOAc=Ethyl acetate

HPLC=High Pressure Liquid Chormatography

NMR=Nuclear Magnetic Resonance

PPTS=Pyridinium p-toluenesulfonate

pTsOH=p-Toluene sulfonic acid

TBAHS or Bu₄NHSO₄=Tetra-n-butylammonium hydrogen sulfate

TEMPO=2,2,6,6,-Tetramethyl-1-piperidinyloxy, free radical

THF=Tetrahydrofuran

As used herein, unless otherwise noted, the term an “androgen modulator”shall mean any compound which exhibits tissue selective agonist and/orantagonist activity. For example, an androgen modulator may be acompound which exhibits agonist activity in muscle tissue and antagonistactivity in prostate tissue (e.g. for the treatment of cachexia).Further, an androgen modulator may be a compound that exhibits varyingamounts of agonist or antagonist activity depending on the tissue type.

The term “subject” as used herein, refers to an animal, preferably amammal, most preferably a human, who has been the object of treatment,observation or experiment.

The term “therapeutically effective amount” as used herein, means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician, which includes alleviation of the symptoms of thedisease or disorder being treated.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombinations of the specified ingredients in the specified amounts.

Where the compounds according to this invention have at least one chiralcenter, they may accordingly exist as enantiomers. Where the compoundspossess two or more chiral centers, they may additionally exist asdiastereomers. It is to be understood that all such isomers and mixturesthereof are encompassed within the scope of the present invention.Furthermore, some of the crystalline forms for the compounds may existas polymorphs and as such are intended to be included in the presentinvention. In addition, some of the compounds may form solvates withwater (i.e., hydrates) or common organic solvents, and such solvates arealso intended to be encompassed within the scope of this invention.

Compounds of formula (I) wherein R¹ is hydrogen and R⁵ is OH may beprepared according to the process outlined in Scheme 1.

Accordingly, a suitably substituted compound of formula (X), a knowncompound or compound prepared by known methods, is reacted with asuitably substituted compound of formula (XI), wherein A¹ is loweralkyl, a known compound or compound prepared by known methods, in thepresence of a Lewis acid such as AlCl(CH₂CH₃)₂, Al(CH₃)₃, TiCl₄, and thelike, in an organic solvent such as toluene, xylenes, and the like, at atemperature greater than about room temperature, preferably at atemperature of about 80° C., more preferably, at about refluxtemperature, to yield the corresponding compound of formula (Ia).

Compounds of formula (I) wherein R¹ is hydrogen and R⁵ is OH mayalternatively be prepared according to the process outlined in Scheme 2below.

Accordingly, a suitably substituted compound of formula (X), a knowncompound or compound prepared by known methods, is reacted with asuitably substituted compound of formula (XII), in the presence of anacid such as HCl, H₂SO₄, HBr, and the like, in water; or in the presenceof polyphosphoric acid (PPA), neat (i.e. in the absence of additionalsolvent); at a temperature greater than about room temperature,preferably at about reflux temperature, to yield the correspondingcompound of formula (XIII).

The compound of formula (XIII) is reacted with a suitably selectedoxidizing agent, to yield the corresponding compound of formula (XIV).For example, the compound of formula (XIII) may be reacted with amixture of bleach and TEMPO, in the presence of a phase transfercatalyst such as TBAHS, in the presence of a salt such as KBr, in atwo-phase mixture of water and organic solvent (such as ethyl acetate,DCM, and the like), to yield the corresponding compound of formula(XIV). Alternatively, the compound of formula (XIII) may be reacted witha mixture of CrO₃ and H₂SO in a solvent such as water, DCM, and thelike, to yield the corresponding compound of formula (XIV).Alternatively still, the compound of formula (XIII) may be reacted withDess-Martin periodinane, in an organic solvent such as DCM, benzene, andthe like, to yield the corresponding compound of formula (XIV).

Preferably, the compound of formula (XIV) is dried to remove anyhydrated water/any hydrate component.

The compound of formula (XIV) is reacted with a suitably substitutedcompound of formula (XV), wherein M is MgCl, MgBr, MgI or Li, a knowncompound or compound prepared by known methods, to yield thecorresponding compound of formula (Ia).

For example, wherein the compound of formula (XV) M is MgCl, MgBr, MgIor Li, the compound of formula (XIV) is reacted with the compound offormula (XV), in an anhydrous organic solvent such as THF, diethylether, and the like, preferably at a temperature less than about roomtemperature, more preferably, at about 0° C., to yield the correspondingcompound of formula (Ia).

Alternatively, wherein the compound of formula (XV) M is Br, thecompound of formula (XIV) is reacted with the compound of formula (XV),in the presence of In metal, in a mixture of an aqueous solution of pHfrom about 7 to about 4, preferably a pH from about 3 to about 4, and anorganic solvent such as ethyl acetate, DCM, and the like, preferably atabout room temperature, to yield the corresponding compound of formula(Ia).

One skilled in the art will recognize that wherein the compound offormula (XIV) is reacted with a compound of formula (XV) wherein M isMgCl, MgBr, MgI or Li, the compound of formula (XIV) is preferably driedprior to the reaction.

Preferably, the compound of formula (XIV) is reacted with a compound offormula (XV) wherein M is MgCl, MgBr, MgI or Li for the preparation ofcompounds of formula (I) wherein R⁴ is alkyl, alkenyl, aryl,(C₂₋₄alkyl)-aryl, heteroaryl or -(lower alkyl)-heteroaryl.

Preferably, the compound of formula (XIV) is reacted with a compound offormula (XV) wherein M is Br for the preparation of compounds of formula(I) wherein R⁴ is alkenyl, —(CH)-alkenyl or —(CH₂)-alkynyl.

Compounds of formula (I) wherein R⁴ and R⁵ are taken together with theatoms to which they are bound to form a ring structure containing oneheteroatom may be prepared according to the process outlined in Scheme 3below.

Accordingly, a suitably substituted compound of formula (X), a knowncompound or compound prepared by known methods, is reacted with asuitably substituted compound of formula (XVI), wherein A¹ is loweralkyl, a known compound or compound prepared by known methods, in thepresence of a Lewis acid such as AlCl(CH₂CH₃)₂, Al(CH₃)₃, TiCl₄, and thelike, in an organic solvent such as toluene, xylenes, and the like, at atemperature greater than about room temperature, preferably at atemperature of about 80° C., more preferably, at about refluxtemperature, to yield the corresponding compound of formula (Ib).

Compounds of formula (I) wherein R⁴ and R⁵ are taken together with theatom to which they are bound to form a ring structure containing two Oheteroatoms may alternatively be prepared according to the processoutlined in Scheme 4 below.

Accordingly, a suitably substituted compound of formula (XVII), a knowncompound or compound prepared according to known methods, is reactedwith a suitably substituted compound of formula (XVIII), wherein R⁰ isselected from the group consisting of hydrogen, lower alkyl, -(loweralkyl)-OH and -(lower alkyl)-(halogen), a known compound or compoundprepared by known methods, in the presence of an inorganic base such asK₂CO₃, Na₂CO₃, Cs₂CO₃, and the like, in an organic solvent such as DMF,DMSO, and the like, to yield the corresponding compounds of formula(Ic).

Compounds of formula (I) wherein R⁴ and R⁵ are taken together with theatom to which they are bound to form a ring structure containing two Nheteroatoms may be prepared according to the process outlined in Scheme5 below.

Accordingly, a suitably substituted compound of formula (XVII), a knowncompound or compound prepared by known methods is reacted with asuitably substituted compound of formula (XIX), wherein R⁰ is selectedfrom the group consisting of hydrogen, lower alkyl, -(lower alkyl)-OHand -(lower alkyl)-(halogen), a known compound or compound prepared byknown methods, in the presence of a catalyst such as pTsOH, PPTS, andthe like, in an organic solvent such as toluene, xylenes, and the like,at a temperature greater than about room temperature, preferably atabout reflux temperature, to yield the corresponding compound of formula(Id).

Compounds of formula (I) wherein R⁴ and R⁵ are taken together with theatom to which they are bound to form a ring structure containing an Oand a N heteroatom may alternatively be prepared according to theprocess outlined in Scheme 6 below.

Accordingly, a suitably substituted compound of formula (XVII) isreacted with a suitably substituted compound of formula (XX), wherein R⁰is selected from the group consisting of hydrogen, lower alkyl, -(loweralkyl)-OH and -(lower alkyl)-(halogen), in the presence of an inorganicbase such as K₂CO₃, Na₂CO₃, Cs₂CO₃, and the like, in an organic solventsuch as DMF, DMSO, and the like, to yield the corresponding compound offormula (Ie).

One skilled in the art will recognize that compounds of formula (I)wherein R⁴ and R⁵ are taken together with the atom to which they arebound to form a ring structure may alternatively be prepared accordingto the processes outlined in Schemes 4, 5 and 6 above, by substituting asuitably substituted compound of formula (XXI)

a known compound or compound prepared by known methods (for example asdescribed in Example 2 which follows herein), for the compound offormula (XVII). One skilled in the art will recognize that the compoundof formula (XXI) will equilibrate with the corresponding compound offormula (XVII) in the presence of water.

Compounds of formula (I) wherein R⁵ is —OR⁶ and R⁶ is other than H canbe prepared from the corresponding compound of formula (Ia), accordingto known methods, for example alkylation, acylation, reacting with asuitably substituted compound of the formula R¹—Br in the presence ofNaH, and the like.

Compounds of formula (I) wherein R¹ is other than H can be prepared fromthe corresponding compound of formula (Ia), according to known methods,for example by alkylation, acylation, sulfonylation, and the like.

One skilled in the art will recognize that wherein a reaction step ofthe present invention may be carried out in a variety of solvents orsolvent systems, said reaction step may also be carried out in a mixtureof the suitable solvents or solvent systems.

Where the processes for the preparation of the compounds according tothe invention give rise to mixture of stereoisomers, these isomers maybe separated by conventional techniques such as preparativechromatography. The compounds may be prepared in racemic form, orindividual enantiomers may be prepared either by enantiospecificsynthesis or by resolution. The compounds may, for example, be resolvedinto their component enantiomers by standard techniques, such as theformation of diastereomeric pairs by salt formation with an opticallyactive acid, such as (−)-di-p-toluoyl-D-tartaric acid and/or(+)-di-p-toluoyl-L-tartaric acid followed by fractional crystallizationand regeneration of the free base. The compounds may also be resolved byformation of diastereomeric esters or amides, followed bychromatographic separation and removal of the chiral auxiliary.Alternatively, the compounds may be resolved using a chiral HPLC column.

During any of the processes for preparation of the compounds of thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, 1991. The protectinggroups may be removed at a convenient subsequent stage using methodsknown from the art.

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds which are readily convertible invivo into the required compound. Thus, in the methods of treatment ofthe present invention, the term “administering” shall encompass thetreatment of the various disorders described with the compoundspecifically disclosed or with a compound which may not be specificallydisclosed, but which converts to the specified compound in vivo afteradministration to the patient. Conventional procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

For use in medicine, the salts of the compounds of this invention referto non-toxic “pharmaceutically acceptable salts.” Other salts may,however, be useful in the preparation of compounds according to thisinvention or of their pharmaceutically acceptable salts. Suitablepharmaceutically acceptable salts of the compounds include acid additionsalts which may, for example, be formed by mixing a solution of thecompound with a solution of a pharmaceutically acceptable acid such ashydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinicacid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonicacid or phosphoric acid. Furthermore, where the compounds of theinvention carry an acidic moiety, suitable pharmaceutically acceptablesalts thereof may include alkali metal salts, e.g., sodium or potassiumsalts; alkaline earth metal salts, e.g., calcium or magnesium salts; andsalts formed with suitable organic ligands, e.g., quaternary ammoniumsalts. Thus, representative pharmaceutically acceptable salts includethe following:

acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate,borate, bromide, calcium edetate, camsylate, carbonate, chloride,clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate,esylate, fumarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate,lactobionate, laurate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate,pantothenate, phosphate/diphosphate, polygalacturonate, salicylate,stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate,tosylate, triethiodide and valerate.

Representative acids and bases which may be used in the preparation ofpharmaceutically acceptable salts include the following:

acids including acetic acid, 2,2-dichloroactic acid, acylated aminoacids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid,benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid,(+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonicacid, capric acid, caproic acid, caprylic acid, cinnamic acid, citricacid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid,ethanesulfonic acid, 2-hydrocy-ethanesulfonic acid, formic acid, fumaricacid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconicacid, D-glucoronic acid, L-glutamic acid, α-oxo-glutaric acid, glycolicacid, hipuric acid, hydrobromic acid, hydrochloric acid, (+)-L-lacticacid, (±)-DL-lactic acid, lactobionic acid, maleic acid, (−)-L-malicacid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid,naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid,1-hydroxy-2-naphthoic acid, nicotinc acid, nitric acid, oleic acid,orotic acid, oxalic acid, palmitric acid, pamoic acid, phosphoric acid,L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebaicacid, stearic acid, succinic acid, sulfuric acid, tannic acid,(+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid andundecylenic acid; and

bases including ammonia, L-arginine, benethamine, benzathine, calciumhydroxide, choline, deanol, diethanolamine, diethylamine,2-(diethylamino)-ethanol, ethanolamine, ethylenediamine,N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, magnesiumhydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassiumhydroxide, 1-(2-hydroxyethyl)-pyrrolidine, secondary amine, sodiumhydroxide, triethanolamine, tromethamine and zinc hydroxide.

The present invention further comprises pharmaceutical compositionscontaining one or more compounds of formula (I) with a pharmaceuticallyacceptable carrier. Pharmaceutical compositions containing one or moreof the compounds of the invention described herein as the activeingredient can be prepared by intimately mixing the compound orcompounds with a pharmaceutical carrier according to conventionalpharmaceutical compounding techniques. The carrier may take a widevariety of forms depending upon the desired route of administration(e.g., oral, parenteral). Thus for liquid oral preparations such assuspensions, elixirs and solutions, suitable carriers and additivesinclude water, glycols, oils, alcohols, flavoring agents, preservatives,stabilizers, coloring agents and the like; for solid oral preparations,such as powders, capsules and tablets, suitable carriers and additivesinclude starches, sugars, diluents, granulating agents, lubricants,binders, disintegrating agents and the like. Solid oral preparations mayalso be coated with substances such as sugars or be enteric-coated so asto modulate major site of absorption. For parenteral administration, thecarrier will usually consist of sterile water and other ingredients maybe added to increase solubility or preservation. Injectable suspensionsor solutions may also be prepared utilizing aqueous carriers along withappropriate additives.

To prepare the pharmaceutical compositions of this invention, one ormore compounds of the present invention as the active ingredient isintimately admixed with a pharmaceutical carrier according toconventional pharmaceutical compounding techniques, which carrier maytake a wide variety of forms depending of the form of preparationdesired for administration, e.g., oral or parenteral such asintramuscular. In preparing the compositions in oral dosage form, any ofthe usual pharmaceutical media may be employed. Thus, for liquid oralpreparations, such as for example, suspensions, elixirs and solutions,suitable carriers and additives include water, glycols, oils, alcohols,flavoring agents, preservatives, coloring agents and the like; for solidoral preparations such as, for example, powders, capsules, caplets,gelcaps and tablets, suitable carriers and additives include starches,sugars, diluents, granulating agents, lubricants, binders,disintegrating agents and the like. Because of their ease inadministration, tablets and capsules represent the most advantageousoral dosage unit form, in which case solid pharmaceutical carriers areobviously employed. If desired, tablets may be sugar coated or entericcoated by standard techniques. For parenterals, the carrier will usuallycomprise sterile water, through other ingredients, for example, forpurposes such as aiding solubility or for preservation, may be included.Injectable suspensions may also be prepared, in which case appropriateliquid carriers, suspending agents and the like may be employed. Thepharmaceutical compositions herein will contain, per dosage unit, e.g.,tablet, capsule, powder, injection, teaspoonful and the like, an amountof the active ingredient necessary to deliver an effective dose asdescribed above. The pharmaceutical compositions herein will contain,per unit dosage unit, e.g., tablet, capsule, powder, injection,suppository, teaspoonful and the like, of from about 0.01-500 mg and maybe given at a dosage of from about 0.05-500 mg/kg/day, preferably fromabout 0.05-10 mg/kg/day, more preferably from about 0.1-5.0 mg/kg/day,or any range therein. The dosages, however, may be varied depending uponthe requirement of the patients, the severity of the condition beingtreated and the compound being employed. The use of either dailyadministration or post-periodic dosing may be employed.

Preferably these compositions are in unit dosage forms from such astablets, pills, capsules, powders, granules, sterile parenteralsolutions or suspensions, metered aerosol or liquid sprays, drops,ampoules, autoinjector devices or suppositories; for oral parenteral,intranasal, sublingual or rectal administration, or for administrationby inhalation or insufflation. Alternatively, the composition may bepresented in a form suitable for once-weekly or once-monthlyadministration; for example, an insoluble salt of the active compound,such as the decanoate salt, may be adapted to provide a depotpreparation for intramuscular injection. For preparing solidcompositions such as tablets, the principal active ingredient is mixedwith a pharmaceutical carrier, e.g. conventional tableting ingredientssuch as corn starch, lactose, sucrose, sorbitol, talc, stearic acid,magnesium stearate, dicalcium phosphate or gums, and otherpharmaceutical diluents, e.g. water, to form a solid preformulationcomposition containing a homogeneous mixture of a compound of thepresent invention, or a pharmaceutically acceptable salt thereof. Whenreferring to these preformulation compositions as homogeneous, it ismeant that the active ingredient is dispersed evenly throughout thecomposition so that the composition may be readily subdivided intoequally effective dosage forms such as tablets, pills and capsules. Thissolid preformulation composition is then subdivided into unit dosageforms of the type described above containing from 0.1 to about 500 mg ofthe active ingredient of the present invention. The tablets or pills ofthe novel composition can be coated or otherwise compounded to provide adosage form affording the advantage of prolonged action. For example,the tablet or pill can comprise an inner dosage and an outer dosagecomponent, the latter being in the form of an envelope over the former.The two components can be separated by an enteric layer which serves toresist disintegration in the stomach and permits the inner component topass intact into the duodenum or to be delayed in release. A variety ofmaterial can be used for such enteric layers or coatings, such materialsincluding a number of polymeric acids with such materials as shellac,cetyl alcohol and cellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude, aqueous solutions, suitably flavoured syrups, aqueous or oilsuspensions, and flavoured emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions, include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatin.

The method of treating disorders or conditions modulated by the androgenreceptor described in the present invention may also be carried outusing a pharmaceutical composition comprising any of the compounds asdefined herein and a pharmaceutically acceptable carrier. Thepharmaceutical composition may contain between about 0.01 mg and 500 mg,preferably about 1 to 100 mg, of the compound, and may be constitutedinto any form suitable for the mode of administration selected. Carriersinclude necessary and inert pharmaceutical excipients, including, butnot limited to, binders, suspending agents, lubricants, flavorants,sweeteners, preservatives, dyes, and coatings. Compositions suitable fororal administration include solid forms, such as pills, tablets,caplets, capsules (each including immediate release, timed release andsustained release formulations), granules, and powders, and liquidforms, such as solutions, syrups, elixers, emulsions, and suspensions.Forms useful for parenteral administration include sterile solutions,emulsions and suspensions.

Advantageously, compounds of the present invention may be administeredin a single daily dose, or the total daily dosage may be administered individed doses of two, three or four times daily. Furthermore, compoundsfor the present invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal skinpatches well known to those of ordinary skill in that art. To beadministered in the form of a transdermal delivery system, the dosageadministration will, of course, be continuous rather than intermittentthroughout the dosage regimen.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Moreover, when desired or necessary,suitable binders; lubricants, disintegrating agents and coloring agentscan also be incorporated into the mixture. Suitable binders include,without limitation, starch, gelatin, natural sugars such as glucose orbeta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth or sodium oleate, sodium stearate, magnesiumstearate, sodium benzoate, sodium acetate, sodium chloride and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum and the like.

The liquid forms in suitably flavored suspending or dispersing agentssuch as the synthetic and natural gums, for example, tragacanth, acacia,methylcellulose and the like. For parenteral administration, sterilesuspensions and solutions are desired. Isotonic preparations whichgenerally contain suitable preservatives are employed when intravenousadministration is desired.

The compound of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine or phophatidylcholines.

Compounds of the present invention may also be delivered by the use ofmonoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds of the present invention may alsobe coupled with soluble polymers as targetable drug carriers. Suchpolymers can include polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamidephenol,polyhydroxy-ethylaspartamidephenol, or polyethyl eneoxidepolylysinesubstituted with palmitoyl residue. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyepsilon caprolactone, polyhydroxy butyeric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross-linked or amphipathic block copolymers of hydrogels.

Compounds of this invention may be administered in any of the foregoingcompositions and according to dosage regimens established in the artwhenever treatment of disorders or conditions modulated by the androgenreceptor is required.

The daily dosage of the products may be varied over a wide range from0.01 to 500 mg per adult human per day. For oral administration, thecompositions are preferably provided in the form of tablets containing,0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150,200, 250 and 500 milligrams of the active ingredient for the symptomaticadjustment of the dosage to the patient to be treated. An effectiveamount of the drug is ordinarily supplied at a dosage level of fromabout 0.01 mg/kg to about 500 mg/kg of body weight per day. Preferably,the range is from about 0.5 to about 10.0 mg/kg of body weight per day,most preferably, from about 0.1 to about 5.0 mg/kg of body weight perday. The compounds may be administered on a regimen of 1 to 4 times perday.

Optimal dosages to be administered may be readily determined by thoseskilled in the art, and will vary with the particular compound used, themode of administration, the strength of the preparation, the mode ofadministration, and the advancement of the disease condition. Inaddition, factors associated with the particular patient being treated,including patient age, weight, diet and time of administration, willresult in the need to adjust dosages.

The following Examples are set forth to aid in the understanding of theinvention, and are not intended and should not be construed to limit inany way the invention set forth in the claims which follow thereafter.

In the Examples which follow, some synthesis products are listed ashaving been isolated as a residue. It will be understood by one ofordinary skill in the art that the term “residue” does not limit thephysical state in which the product was isolated and may include, forexample, a solid, an oil, a foam, a gum, a syrup, and the like.

Example 1 1-(5,6-Dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanol

A 1-L 4-neck flask equipped with a thermocouple controller, an overheadmechanical stirrer, a condenser, and a nitrogen inlet/outlet adaptor wascharged with 4,5-dichloro-1,2-phenylenediamine (71.3 g, 0.403 mol),trifluorolactic acid (87.0 g, 0.604 mol) and 4N HCl (340 mL). Thereaction mixture was heated for 18 h at reflux (100° C.). The resultingsolution was cooled to room temperature and then diluted with EtOAc (1L) and H₂O (1 L). The solution was slowly treated with NaHCO₃ (500 g)until pH 8-9. After the effervescence ceased, the phases were split andaqueous layer was back extracted with EtOAc (3×1 L). The combine organicphase was washed with H₂O (1 L) and brine (1 L); dried over MgSO₄,filtered and evaporated to dryness to yield a crude residue. The cruderesidue was purified by flash chromatography using SiO₂ (2 kg) and 10%EtOAc/CH₂Cl₂ (2 L) and 20% EtOAc/CH₂Cl₂ (32 L) and the product dried invacuo for 18 h at 60° C. to yield the title compound as a brownishsolid.

Example 21-(5,6-Dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone

A 3-L 4-neck flask equipped with a thermocouple controller, an overheadmechanical stirrer, an addition funnel, and a nitrogen inlet/outletadaptor was charged with1-(5,6-dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanol (91.0 g,0.32 mol), 4-methoxy-TEMPO (14.3 g, 0.077 mol), and KBr (4 g, 0.0336mol) in THF (900 mL). The brown homogenous solution was stirred for 15min while cooling to −10° C. After cooling, NaOCl (670 ml) was addeddropwise over a ½h period. The reaction mixture was diluted with EtOAc(1.5 L) and H₂O (1.5 L). When the effervescence ceased, the phases weresplit and the aqueous layer was back extracted with EtOAc (2 L). Thecombined organic layer was washed with brine (2 L); dried over Na₂SO₄,filtered and evaporated to dryness to yield a crude residue. The cruderesidue was purified by flash chromatography using SiO₂ (1 kg) and 40%EtOAc/hexanes (24 L) and the product dried in vacuo for 18 h at 50° C.to yield 1-(5,6-dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanoneas a yellow solid.

Example 32-(5,6-Dichloro-1H-benzoimidazol-2-yl)-1,1,1-trifluoro-pent-4-en-2-ol(#1)

1-(5,6-Dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (1.41 g;4.99 mmol), allyl bromide (0.85 mL; 10.05 mmol) and indium (1.15 g;10.05 mmol) were suspended in THF (50 mL) and 0.01 M HCl (150 mL) andstirred vigorously over 18 hours. The layers were separated and theaqueous layer was extracted with ethyl acetate (3×30 mL). The combinedextracts were washed with brine (50 mL) and dried over Na₂SO₄. Theresulting crude brown oil was purified by column chromatography (SiO₂;20% ethyl acetate/hexanes) to yield the title compound as a tan solid.

¹H NMR (400 MHz, CD₃CN): δ 7.79 (s, 2H), δ 5.59 (m, 1H), δ 5.17 (d,J=17.1 Hz, 1H), δ 5.07 (d, J=11 Hz, 1H), δ 3.13 (dd, J=6.8, 14.3 Hz,1H), δ 2.88 (dd, J=7.2, 14.3 Hz, 1H)

MS calculated for C₁₂H₉Cl₂F₃N₂O: 325.11

MS measured: 325, 327 (M+H); 323, 325 (M−1).

(+)-Enantiomer of2-(5,6-Dichloro-1H-benzoimidazol-2-yl)-1,1,1-trifluoro-pent-4-en-2-ol(#23) and (−)-Enantiomer of2-(5,6-Dichloro-1H-benzoimidazol-2-yl)-1,1,1-trifluoro-pent-4-en-2-ol(#24)

A portion of the product prepared according to the procedure describedabove was dissolved in 20% isopropanol/hexane and chromatographed usinga ChiralPak AD 5×50 cm column (70 mL/min flow rate, mobile phase 10%isopropanol/hexane) with the (+)-enantiomer (#23) eluting first followedby the (−) enantiomer (#24). ¹H NMR and Mass Spectral data for the twoisolated compounds was identical to of Compound #1 isolated above.

Example 42-(5,6-Dichloro-1H-benzoimidazol-2-yl)-1,1,1-trifluoro-penta-3,4-dien-2-ol(#3) and2-(5,6-Dichloro-1H-benzoimidazol-2-yl)-1,1,1-trifluoro-pent-4-yn-2-ol(#2)

1-(5,6-Dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (1.42 g;5.03 mmol), propargyl bromide (80% in toluene; 1.10 mL; 15.4 mmol) andindium (1.56 g; 13.6 mmol) were suspended in THF (50 mL) and 0.01 M HCl(150 mL) and stirred vigorously over 18 hours. The layers were separatedand the aqueous layer was extracted with ethyl acetate (3×30 mL). Thecombined extracts were washed with brine (50 mL) and dried over Na₂SO₄.The resulting crude brown oil was a mixture of2-(5,6-dichloro-1H-benzoimidazol-2-yl)-1,1,1-trifluoro-penta-3,4-dien-2-oland2-(5,6-dichloro-1H-benzoimidazol-2-yl)-1,1,1-trifluoro-pent-4-yn-2-olthat was purified by column chromatography (SiO₂; 20% ethylacetate/hexanes).

2-(5,6-Dichloro-1H-benzoimidazol-2-yl)-1,1,1-trifluoro-penta-3,4-dien-2-olwas isolated as a light yellow solid

¹H NMR (300 MHz, CD₃CN): δ 7.82 (s, 2H), δ 5.93 (t, J=6.7 Hz, 1H), δ5.16 (d, J=6.6 Hz, 1H)

MS calculated for C₁₂H₇Cl₂F₃N₂O: 323.10

MS measured: 323, 325 (M+H); 321, 323 (M−1).

2-(5,6-dichloro-1H-benzoimidazol-2-yl)-1,1,1-trifluoro-pent-4-yn-2-olwas isolated as an orange-yellow solid

¹H NMR (400 MHz, CD₃CN): δ 7.82 (s, 2H), δ 3.35 (dd, J=2.6, 16.8 Hz,1H), δ 3.11 (dd, J=2.6, 17.0 Hz, 1H), δ 5.59 (m, 1H), δ 2.18 (s, 1H)

MS calculated for C₁₂H₇Cl₂F₃N₂O: 323.10

MDS measured: 323, 325 (M+H); 321, 323 (M−1).

(+)-Enantiomer of2-(5,6-Dichloro-1H-benzoimidazol-2-yl)-1,1,1-trifluoro-penta-3,4-dien-2-ol(#31) and (−)-Enantiomer of2-(5,6-Dichloro-1H-benzoimidazol-2-yl)-1,1,1-trifluoro-penta-3,4-dien-2-ol(#32)

A portion of the isolated Compound #2 product prepared according to theprocedure described above was dissolved in 20% ethanol/heptane andchromatographed using a ChiralPak AD 5×50 cm column (70 mL/min flowrate, mobile phase 20% ethanol/heptane) with the (+)-enantiomer (#31)eluting first followed by the (−) enantiomer (#32). ¹H NMR and MassSpectral data for the two isolated compounds was identical to ofCompound #2 isolated above.

Example 52-(5,6-Dichloro-1H-benzoimidazol-2-yl)-1,1,1-trifluoro-but-3-en-2-ol(#4)

To 1-(5,6-dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (326mg) in THF (10 mL) −78° C. was added vinyl magnesium bromide (2.42 mL of1.0 M in THF) dropwise. The resulting mixture was then stirred at 0° C.for 2 hr. The resulting mixture was quenched with H₂O and 1 N HCl,extracted with EtOAc, dried over Na₂SO₄, filtered, and concentrated toyield a residue. The residue was purified by flash chromatography withBiotage 40s+ column and elution with 10%-40% EtOAc/hexanes to yield ayellow gum. The yellow gum was dissolved in a minimal amount of CH₂Cl₂and triturated with hexanes to yield the title compound as a lightyellow solid.

¹H NMR (300 MHz, d₆-DMSO): δ 13.03 (br s, 1H), 7.99 (s, 1H), 7.76 (s,1H), 7.69 (s, 1H), 6.54 (dd, 1H, J=10.8, 17.2 Hz), 5.71 (d, 1H, J=17.2Hz), 5.59 (d, 1H, J=10.8 Hz)

MS (M−1)=309.

Example 62-(5,6-Dichloro-1H-benzoimidazol-2-yl)-1,1,1-trifluoro-3-methyl-pent-3,4-dien-2-ol(#6)

1-(5,6-Dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (0.61 g;2.2 mmol), 1-bromo-2-butyne (1.7 mL; 18.8 mmol) and indium (2.49 g; 21.7mmol) were suspended in THF (10 mL) and 0.045 M HCl (20 mL) and stirredvigorously overnight. The reaction mixture was diluted with water (60mL) and ethyl acetate (40 mL), the layers were separated and the aqueouslayer was extracted with ethyl acetate (3×20 mL). The combined extractswere washed with brine (50 mL) and dried over Na₂SO₄. The resultingcrude material was purified by column chromatography (SiO₂; 20% ethylacetate/hexanes) to yield the title compound as an off-white solid.

¹H NMR (400 MHz, CDCl₃): δ 7.76 (s, 2H), δ 5.08 (m, 2H), δ 1.88 (s, 3H)

MS calculated for C₁₃H₉Cl₂F₃N₂O: 337.12

MS measured: 337, 339 (M+H); 335, 337 (M−1).

Compound #33 (also known as2-(5,6-dichloro-1H-benzoimidazol-2-yl)-1,1,1-trifluoro-hex-4-yn-2-ol)was prepared as a minor by-product of the above described reaction andisolated as a residue.

Example 73-(5,6-Dichloro-1H-benzoimidazol-2-yl)-4,4,4-trifluoro-3-hydroxy-butyronitrile(#7)

To a solution of dry acetonitrile (0.4 mL) in THF (10 mL) at −78° C. wasadded n-BuLi (2.9 mL of 2.5 M in hexanes). The resulting mixture wasstirred for 45 min. at −78° C. To the solution was then added a solutionof 1-(5,6-dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (930mg) in THF (5 mL). The resulting mixture was stirred at −78° C. for 1hr. The reaction was quenched with NH₄Cl (aq) and the resulting mixtureextracted with EtOAc. The combined extracts were washed with brine anddried over Na₂SO₄. The resulting crude material was purified by columnchromatography (SiO₂; 0-15% ethyl acetate/hexanes) to yield the titlecompound as a yellow solid.

¹H NMR (300 MHz, d₆-DMSO): δ 13.31 (br, 1H), 8.48 (s, 1H), 8.04 (s, 1H),7.73 (s, 1H), 3.59 (ABq, 2H, J_(AB)=16.9 Hz, Δν_(AB)=59 Hz).

Example 82-(5,6-Dichloro-1H-benzoimidazol-2-yl)-1,1,1-trifluoro-pent-3-yn-2-ol(#8)

To 1-(5,6-dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (535mg) in THF (10 mL) at −78° C. was added 1-propynyl magnesium bromide (8mL of 0.5 M in THF) dropwise. The resulting mixture was then stirred at0° C. for 3 hr. The reaction was quenched with H₂O and 1 N HCl,extracted with EtOAc, dried over Na₂SO₄, filtered, and concentrated toyield a residue. The residue was purified by flash chromatography withBiotage 40s+ column and elution with 10%-40% EtOAc/hexanes to yield ayellow solid. The yellow solid was dissolved in a minimal amount ofCH₂Cl₂ and triturated with hexanes to yield the title compound as awhite solid.

¹H NMR (300 MHz, d₆-DMSO): δ 13.10 (br s, 1H), 8.48 (s, 1H), 8.01 (s,1H), 7.69 (s, 1H), 1.97 (s, 3H).

MS (M−1)=321.1

Example 92-(5,6-Dichloro-1H-benzoimidazol-2-yl)-1,1,1-trifluoro-3-methyl-but-3-en-2-ol(#9)

To 1-(5,6-dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (793mg) in THF (5 mL) at −78° C. was added isopropenyl magnesium bromide(12.3 mL of 0.5 M in THF) dropwise. The resulting mixture was thenstirred at 0° C. for 5 hr. The reaction was quenched with H₂O and 1 NHCl, extracted with EtOAc, dried over Na₂SO₄, filtered, and concentratedto a residue. The residue was purified by flash chromatography withBiotage 40s+ column and elution with 10%-40% EtOAc/hexanes to yield anorange gum. The orange gum was dissolved in a minimal amount of CH₂Cl₂and triturated with hexanes to yield the title compound as apeach-colored solid.

¹H NMR (400 MHz, d₄-MeOD): δ 7.75 (br, 2H), 5.42 (s, 1H), 5.31 (s, 1H),1.81 (s, 3H), NH and OH protons were not observed.

Example 101-(5,6-Dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-1-phenyl-ethanol(#10)

To 1-(5,6-dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (595mg) in THF (5 mL) at −78° C. was added phenyl magnesium bromide (4.6 mLof 1 M in THF) dropwise. The resulting mixture was stirred at 0° C. for4 hr. The reaction was quenched with H₂O and 1 N HCl, extracted withEtOAc, dried over Na₂SO₄, filtered, and concentrated to a residue. Theresidue was purified by flash chromatography with Biotage 40s+ columnand elution with 10%-40% EtOAc/hexanes to yield a yellow solid. Theyellow solid was dissolved in a minimal amount of CH₂Cl₂ and trituratedwith hexanes to yield the title compound as a tan solid.

MS calculated for C₁₅H₉Cl₂F₃N₂O: 360.00. found: 361 (M+1).

Example 112-(5,6-Dichloro-1H-benzoimidazol-2-yl)-1,1,1-trifluoro-4-methyl-pent-4-en-2-ol(#13)

To 1-(5,6-dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (609mg) in THF (4 mL) and H₂O (12 mL) at room temperature were added3-bromo-2-methyl-propene (0.31 mL), followed by indium powder (279 mg,−100 mesh). The resulting mixture was then stirred at room temperaturefor 18 hr. The resulting mixture was filtered through a pad of Celite®,rinsed with EtOAc, the layers separated, the aqueous layer extractedwith EtOAc, dried over Na₂SO₄, filtered, and concentrated to yield aresidue. The residue was purified by flash chromatography with Biotage40s+ column and elution with 10%-40% EtOAc/hexanes to yield an orangegum. The orange gum was dissolved in a minimal amount of CH₂Cl₂ andtriturated with hexanes to yield the title compound as an orange solid.

¹H NMR (400 MHz, d₄-MeOD): δ 7.78 (br, 1H), 7.69 (br, 1H), 4.73 (s, 1H),4.69 (s, 1H), 2.98 (ABq, 2H, J_(AB)=14.3 Hz, Δν_(AB)=120.4 Hz), 1.54 (s,3H), NH and OH protons were not observed.

Example 122-(5,6-Dichloro-1H-benzoimidazol-2-yl)-1,1,1-trifluoro-4-methyl-pent-3-en-2-ol(#14)

To 1-(5,6-dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (565mg) in THF (5 mL) at 0° C. was added Grignard reagent, which was freshlyprepared from 1-bromo-2-methyl-propene (0.51 mL), a small iodine flake,and magnesium powder (146 mg) in THF (5 mL). The resulting mixture wasthen stirred at room temperature for 3 hr. The reaction was quenchedwith NH₄Cl (sat. aq), filtered through a pad of Celite®, rinsed withEtOAc, the layers were separated, the aqueous layer extracted withEtOAc, dried over Na₂SO₄, filtered, and concentrated to yield a residue.The residue was purified by flash chromatography with Biotage 40s+column and elution with 10%-40% EtOAc/hexanes to yield a yellow solid.The yellow solid was dissolved in a minimal amount of CH₂Cl₂ andtriturated with hexanes to yield the title compound as a yellow solid.

¹H NMR (400 MHz, d₄-MeOD): δ 7.73 (br, 2H), 5.91 (s, 1H), 1.84 (s, 3H),1.46 (s, 3H), NH and OH protons were not observed.

MS (M+1)=339.0

Example 132-(5,6-Dichloro-1H-benzoimidazol-2-yl)-1,1,1-trifluoro-cis-pent-3-en-2-ol(#15)

To 1-(5,6-dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (510mg) in THF (5 mL) at 0° C. was added Grignard reagent, which was freshlyprepared from cis-1-bromo-1-propene (1.07 mL), a small iodine flake, andmagnesium powder (306 mg) in THF (5 mL). The resulting mixture was thenstirred at room temperature for 3 hr. The reaction was quenched withNH₄Cl (sat. aq), filtered through a pad of Celite®, rinsed with EtOAc,the layers were separated, the aqueous layer extracted with EtOAc, driedover Na₂SO₄, filtered, and concentrated to yield a residue. The residuewas purified by flash chromatography with Biotage 40s+ column andelution with 10%-40% EtOAc/hexanes to yield a yellow solid. The yellowsolid was dissolved in a minimal amount of CH₂Cl₂ and triturated withhexanes to yield the title compound as a yellow solid.

¹H NMR (400 MHz, d₄-MeOD): δ 7.77 (br, 1H), 7.72 (br, 1H), 6.07-6.12 (m,1H), 6.01-6.05 (m, 1H), 1.52 (dd, 3H, J=1.2, 6.9 Hz), NH and OH protonswere not observed.

MS (M+1)=325.1

Example 142-(5,6-Dichloro-1H-benzoimidazol-2-yl)-1,1,1-trifluoro-trans-pent-3-en-2-ol(#16)

To 1-(5,6-dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (636mg) in THF (5 mL) at 0° C. was added Grignard reagent, which was freshlyprepared from trans-1-bromo-1-propene (1.35 mL), a small iodine flake,and magnesium powder (382 mg) in THF (5 mL). The resulting mixture wasthen stirred at room temperature for 3 hr. The reaction was quenchedwith NH₄Cl (sat. aq), filtered through a pad of Celite®, rinsed withEtOAc, the layers were separated, the aqueous layer extracted withEtOAc, dried over Na₂SO₄, filtered, and concentrated to yield a residue.The residue was purified by flash chromatography with Biotage 40s+column and elution with 10%-40% EtOAc/hexanes to yield a yellow solid.The yellow solid was dissolved in a minimal amount of CH₂Cl₂ andtriturated with hexanes to yield the title compound as a yellow solid.

¹H NMR (400 MHz, d₄-MeOD): δ 7.79 (br, 1H), 7.71 (br, 1H), 6.13 (s, 1H),6.11-6.13 (m, 1H), 1.82 (apparent d, 3H, J=4.9 Hz), NH and OH protonswere not observed

MS (M+1)=325.1.

Example 154-(5,6-Dichloro-1H-benzoimidazol-2-yl)-5,5,5-trifluoro-pent-2-yne-1,4-diol(#17)

To 1-(5,6-dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (3.2g) in THF (40 mL) at 0° C. was added lithium reagent which was freshlyprepared from tetrahydropyran-2-propynyloxy (1.6 mL) and n-BuLi (4.5 mLof 2.5 M in hexanes) in THF (20 mL) (stirred at −78° C. for 2 h). Theresulting mixture was then stirred at room temperature for 3 hr. Thereaction was quenched with NH₄Cl (sat. aq), filtered through a pad ofCelite®, rinsed with EtOAc, the layer were separated, the aqueous laterextracted with EtOAc, dried over Na₂SO₄, filtered, and concentrated toyield a residue. The residue was purified by flash chromatography withBiotage 40m+ column and elution with 5%-30% EtOAc/hexanes to an orangesolid.

To a solution of THP ether (2.28 g, see procedure above) in methanol (25mL) was added p-toluenesulfonic acid monohydrate (2.05 g) and theresulting mixture stirred at room temperature for 2 h. The reactionmixture was then quenched with Na₂CO₃ (aq), extracted with EtOAc, anddried over Na₂SO₄ to yield a residue. The residue was purified by flashchromatography with Biotage 40s+ column and elution with 5%-35%EtOAc/hexanes to yield the title compound as an orange solid.

¹H NMR (300 MHz, d₆-DMSO): δ 13.16 (br, 1H), 8.66 (br, 1H), 8.01 (s,1H), 7.69 (s, 1H), 5.46 (t, 1H, J=6.1 Hz), 4.23 (d, 2H, J=6.0 Hz)

MS (M+1)=339.

Example 162-(5,6-Dichloro-1H-benzoimidazol-2-yl)-1,1,1-trifluoro-3,3-dimethyl-pent-4-en-2-ol(#25)

1-(5,6-Dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (0.31 g;1.09 mmol), 3,3-dimethylallyl bromide (90%; 1.40 mL; 10.8 mmol) andindium (1.26 g; 11.0 mmol) were suspended in THF (10 mL) and 0.02 M HCl(15 mL) and stirred vigorously over 18 hours. The reaction mixture wasthen diluted with water (60 mL) and ethyl acetate (40 mL), the layerswere separated and the aqueous layer was extracted with ethyl acetate(3×20 mL). The combined extracts were washed with brine (50 mL) anddried over Na₂SO₄ to yield a crude oil. The crude oil was purified bycolumn chromatography (SiO₂; 20% ethyl acetate/hexanes) to yield thetitle compound as an off-white solid.

¹H NMR (400 MHz, CD₃CN): δ 7.88 (s, 2H), 6.18 (dd, 1H, J=1.3, 10.9 Hz),5.14 (m, 2H), 1.19 (s, 3H), 1.17 (s, 3H)

MS calculated for C₁₄H₁₃Cl₂F₃N₂O: 353.17

MS measured: 353, 355 (M+H); 351, 353 (M−1).

Example 172-(5,6-Dichloro-1H-benzoimidazol-2-yl)-1,1,1-trifluoro-3-methyl-pent-4-en-2-ol(#26)

1-(5,6-Dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (0.31 g;1.09 mmol), crotyl bromide (1.2 mL; 11.8 mmol) and indium (1.26 g; 11.0mmol) were suspended in THF (10 mL) and 0.02 M HCl (15 mL) and stirredvigorously over 18 hours. The reaction mixture was then diluted withwater (60 mL) and ethyl acetate (40 mL), the layers were separated andthe aqueous layer was extracted with ethyl acetate (3×20 mL). Thecombined extracts were washed with brine (50 mL) and dried over Na₂SO₄to yield a crude oil. The crude oil was purified by columnchromatography (SiO₂; 20% ethyl acetate/hexanes) to yield the titlecompound as a 2:1 mixture of diastereomers as an off-white solid.

¹H NMR (400 MHz, CD₃CN): δ 7.88 (s, 2H), (Mixture of diastereomers) δ5.92 and δ 5.78 (m, 1H), (Mixture of diastereomers) δ 5.26 and δ 4.99(d, J=17.1 Hz, 1H), (Mixture of diastereomers) δ 5.17 and δ 4.92 (d,J=10.3 Hz, 1H), (Mixture of diastereomers) δ 3.26 and δ 3.18 (m, 1H),(Mixture of diastereomers) δ 1.16 and δ 0.86 (d, J=6.9 Hz, 3H)

MS calculated for C₁₃H₁₁Cl₂F₃N₂O: 339.14

MS measured: 339, 341 (M+H); 337, 339 (M−1)

Example 182-[2-(5,6-Dichloro-1H-benzoimidazol-2-yl)-3,3,3-trifluoro-2-hydroxy-propyl]-acrylicacid (#27)

1-(5,6-Dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (0.30 g;1.05 mmol), 2-(bromomethyl) acrylic acid (1.80 g; 10.9 mmol) and indium(1.23 g; 10.7 mmol) were suspended in THF (10 mL) and 0.02 M HCl (15 mL)and stirred vigorously over 18 hours. The reaction mixture was thendiluted with water (60 mL) and ethyl acetate (40 mL), the layers wereseparated and the aqueous layer was extracted with ethyl acetate (3×20mL). The combined extracts were washed with brine (50 mL) and dried overNa₂SO₄ to yield a crude material. The crude material was purified bycolumn chromatography (SiO₂; 50% ethyl acetate/hexanes) to yield thetitle compound as an off-white solid.

¹H NMR (400 MHz, CD₃CN): δ 7.78 (s, 2H), 6.16 (s, 1H), 5.69 (s, 1H),3.75 (d, J=10.4 Hz, 1H), 3.67 (d, J=10.3 Hz, 1H)

MS calculated for C₁₃H₉Cl₂F₃N₂O₃: 369.12

MS measured: 369, 371 (M+H); 367, 369 (M−1).

Example 192-(5,6-Dichloro-1H-benzoimidazol-2-yl)-1,1,1-trifluoro-3-phenyl-pent-4-en-2-ol(#28)

1-(5,6-Dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (0.30 g;1.04 mmol), cinnamyl bromide (1.6 mL; 10.5 mmol) and indium (1.22 g;10.7 mmol) were suspended in THF (10 mL) and 0.02 M HCl (15 mL) andstirred vigorously over 18 hours. The reaction mixture was then dilutedwith water (60 mL) and ethyl acetate (40 mL), the layers were separatedand the aqueous layer was extracted with ethyl acetate (3×20 mL). Thecombined extracts were washed with brine (50 mL) and dried over Na₂SO₄to yield a crude oil. The crude oil was purified by columnchromatography (SiO₂; 20% ethyl acetate/hexanes) to yield the titlecompound as an off-white solid.

¹H NMR (400 MHz, CD₃CN): δ 10.63 (br s, 1H), 7.77 (s, 1H), 7.55 (s, 1H),7.14 (m, 2H), 7.06 (m, 3H), 6.47 (dd, J=10.0, 18.7 Hz, 1H), 5.32 (m,2H), 5.24 (dd, J=1.5, 10.2 Hz, 1H), 4.35 (d, J=9.9 Hz, 1H)

MS calculated for C₁₈H₁₃Cl₂F₃N₂O: 401.21

MS measured: 401, 403 (M+H); 399, 401 (M−1).

Example 202-(5,6-Dichloro-1H-benzoimidazol-2-yl)-1,1,1-trifluoro-5-phenyl-pent-4-yn-2-ol(#34)

2-(5,6-Dichloro-1H-benzoimidazol-2-yl)-1,1,1-trifluoro-pent-4-yn-2-ol(0.27 g; 0.83 mmol), iodobenzene (0.14 mL; 1.3 mmol),dichlorobis(triphenylphosphine)palladium (31.7 mg; 0.045 mmol), copperiodide (17.8 mg; 0.093 mmol) and triethylamine (0.25 mL; 1.8 mmol) weresuspended in THF (5 mL) and the resulting mixture stirred vigorouslyovernight. The reaction mixture was then concentrated in vacuo and theresulting crude brown oil was purified by column chromatography (SiO₂;50% ether/CH₂Cl₂) to yield the title compound as an orange-yellow solid.

¹H NMR (400 MHz, CD₃CN): δ 7.90 (s, 1H), 7.75 (s, 1H), 7.29 (m, 3H),7.21 (m, 2H), 3.54 (d, J=17.1 Hz, 1H), 3.33 (d, J=17.1 Hz, 1H)

MS calculated for C₁₈H₁₁Cl₂F₃N₂O: 399.19

MS measured: 399, 401 (M+H); 397, 399 (M−1).

Example 212-(1-Hydroxy-1-trifluoromethyl-but-3-enyl)-6-trifluoromethyl-1H-benzoimidazole-5-carbonitrile(#38)

2-(2,2,2-Trifluoro-acetyl)-6-trifluoromethyl-1H-benzoimidazole-5-carbonitrile(0.31 g; 0.95 mmol), allyl bromide (0.82 mL; 9.5 mmol) and indium (1.09g; 9.5 mmol) were suspended in THF (12 mL) and 0.03 M HCl (10 mL) andstirred vigorously overnight. The reaction mixture was then diluted withwater (60 mL) and ethyl acetate (40 mL), the layers were separated andthe aqueous layer was extracted with ethyl acetate (3×20 mL). Thecombined extracts were washed with brine (50 mL) and dried over Na₂SO₄to yield a crude material. The crude material was purified by columnchromatography (SiO₂; 20% ethyl acetate/hexanes) to yield the titlecompound as an off-white solid.

¹H NMR (400 MHz, CD₃CN): δ 8.25 (s, 1H), 8.12 (s, 1H), 5.58 (m, 1H),5.17 (m, 1H), 5.07 (m, 1H), 3.17 (dd, J=7.1, 14.3 Hz, 1H), 2.93 (dd,J=7.2, 14.3 Hz, 1H)

MS calculated for C₁₄H₉F₆N₃O: 349.23

MS measured: 350 (M+H); 348 (M−1).

Example 222-(1-Hydroxy-1-trifluoromethyl-but-3-ynyl)-6-trifluoromethyl-1H-benzoimidazole-5-carbonitrile(#39)

2-(2,2,2-Trifluoro-acetyl)-6-trifluoromethyl-1H-benzoimidazole-5-carbonitrile(0.31 g; 0.94 mmol), propargyl bromide (80% in toluene; 1.1 mL; 12.3mmol) and indium (1.08 g; 9.5 mmol) were suspended in THF (12 mL) and0.03 M HCl (10 mL) and stirred vigorously overnight. The reactionmixture was then diluted with water (60 mL) and ethyl acetate (40 mL),the layers were separated and the aqueous layer was extracted with ethylacetate (3×20 mL). The combined extracts were washed with brine (50 mL)and dried over Na₂SO₄ to yield a crude material. The crude material waspurified by column chromatography (SiO₂; 20% ethyl acetate/hexanes) toyield the title compound as an off-white solid.

¹H NMR (400 MHz, CD₃CN): δ 8.29 (s, 1H), δ 8.15 (s, 1H), 3.39 (dd,J=2.6, 17.1 Hz, 1H), 3.15 (dd, J=2.7, 17.1 Hz, 1H), 2.20 (t, J=2.7 Hz,1H)

MS calculated for C₁₄H₇F₆N₃O: 347.22

MS measured: 348 (M+H); 346 (M−1)

Example 232-(5,6-Dichloro-1H-benzoimidazol-2-yl)-1,1,1-trifluoro-hex-5-en-2-ol(#40)

To 1-(5,6-dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (595mg) in THF (3 mL) at −78° C. was added 3-butenyl magnesium bromide (7.8mL of 0.5 M in THF) dropwise. The resulting mixture was then stirred at0° C. for 4 hr. The reaction was quenched with H₂O and 1 N HCl,extracted with EtOAc, dried over Na₂SO₄, filtered, and concentrated toyield a residue. The residue was purified by flash chromatography withBiotage 40s+ column and elution with 10%-40% EtOAc/hexanes to yield ayellow solid. The yellow solid was dissolved in a minimal amount of Et₂Oand triturated with hexanes to yield the title compound as a tan solid.

¹H NMR (300 MHz, d₆-DMSO): δ 12.95 (br s, 1H), 7.94 (s, 1H), 7.73 (s,1H), 7.41 (s, 1H), 5.53-5.81 (m, 1H), 4.89-5.00 (m, 2H), 2.36-2.44 (m,1H), 1.99-2.23 (m, 2H), 1.62-1.72 (m, 1H)

MS (M+1)=339.0

Example 242-(1-Hydroxy-2-methyl-1-trifluoromethyl-buta-2,3-dienyl)-6-trifluoromethyl-1H-benzoimidazole-5-carbonitrile(#41)

2-(2,2,2-Trifluoro-acetyl)-6-trifluoromethyl-1H-benzoimidazole-5-carbonitrile(0.31 g; 0.94 mmol), 1-bromo-2-butyne (0.85 mL; 9.4 mmol) and indium(1.09 g; 9.5 mmol) were suspended in THF (12 mL) and 0.03 M HCl (10 mL)and stirred vigorously overnight. The reaction mixture was then dilutedwith water (60 mL) and ethyl acetate (40 mL), the layers were separatedand the aqueous layer was extracted with ethyl acetate (3×20 mL). Thecombined extracts were washed with brine (50 mL) and dried over Na₂SO₄to yield a crude material. The crude material was purified by columnchromatography (SiO₂; 20% ethyl acetate/hexanes) to yield the titlecompound as a white solid.

¹H NMR (400 MHz, CD₃CN): δ 8.27 (s, 1H), 8.13 (s, 1H), 5.00 (dd, J=3.1,6.2 Hz, 1H), 1.71 (s, 3H)

MS calculated for C₁₅H₉F₆N₃O: 361.24

MS measured: 362 (M+H); 360 (M−1)

Example 252-(5,6-Dichloro-1H-benzoimidazol-2-yl)-1,1,1-trifluoro-3,4-dimethyl-pent-3-en-2-ol(#42)

To 1-(5,6-dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (577mg) in THF (5 mL) at 0° C. was added Grignard reagent, which was freshlyprepared from 2-bromo-3-methyl-2-butene (1.73 mL), a small iodine flake,and magnesium powder (347 mg) in THF (5 mL). The resulting mixture wasstirred at room temperature for 3 hr. The reaction was quenched withNH₄Cl (sat. aq), filtered through a pad of Celite®, rinsed with EtOAc,the layers were separated, the aqueous layer extracted with EtOAc, driedover Na₂SO₄, filtered, and concentrated to yield a residue. The residuewas purified by flash chromatography with Biotage 40s+ column andelution with 10%-40% EtOAc/hexanes to yield a yellow solid. The yellowsolid was dissolved in a minimal amount of CH₂Cl₂ and triturated withhexanes to yield the title compound as an off-white solid.

¹H NMR (400 MHz, d₄-MeOD): δ 7.78 (s, 1H), 7.66 (s, 1H), 1.97 (s, 3H),1.77 (s, 3H), 1.34 (s, 3H), NH and OH protons were not observed.

MS (M+1)=353.0

Example 26(+)-2-(5,6-dichloro-1H-benzoimidazol-2-yl)-1,1,1-trifluoro-but-3-en-2-ol(#43) and(−)-2-(5,6-dichloro-1H-benzoimidazol-2-yl)-1,1,1-trifluoro-but-3-en-2-ol(#44)

2-(5,6-Dichloro-1H-benzoimidazol-2-yl)-1,1,1-trifluoro-but-3-en-2-olproduct (285 mg) was then separated into the (+) and (−) enantiomers viaHPLC on Chiralpak AD (5×50 cm), using 7% isopropanol in heptane as theeluent (70 mL/min).

¹H NMR (300 MHz, d₆-DMSO): δ 13.03 (br s, 1H), 7.99 (s, 1H), 7.76 (s,1H), 7.69 (s, 1H), 6.54 (dd, 1H, J=10.8, 17.2 Hz), 5.71 (d, 1H, J=17.2Hz), 5.59 (d, 1H, J=10.8 Hz)

MS (M−1)=309.

(+)-2-(5,6-dichloro-1H-benzoimidazol-2-yl)-1,1,1-trifluoro-but-3-en-2-ol(#43

[α]_(CHCl3)=+105 (c=0.5 g/100 mL)

(−)-2-(5,6-dichloro-1H-benzoimidazol-2-yl)-1,1,1-trifluoro-but-3-en-2-ol(#44

[α]_(CHCl3)=−108 (c=0.5 g/100 mL)

Example 27 2-Hydroxy-2-trifluoromethyl-but-3-enoic acid ethyl ester

To a solution of ethyl 3,3,3-trifluoropyruvate (14.2 g) in THF (200 mL)at −78° C. was added vinyl magnesium bromide (84 mL of 1M in THF)dropwise via addition funnel. The resulting mixture was then warmed toambient temperature over 2 h. The reaction was quenched by pouring themixture over ice. To the resulting mixture was then added 2 N HCl, themixture was extracted with EtOAc, and dried over Na₂SO₄. Afterconcentration, the resulting crude material was filtered through a plugof silica gel and rinsed with 50% Et₂O/hexanes. The resulting mixturewas concentrated to yield the title compound as a golden oil.

Example 28 2-Allyloxy-2-trifluoromethyl-but-3-enoic acid ethyl ester

To a solution of 2-hydroxy-2-trifluoromethyl-but-3-enoic acid ethylester (3.6 g) in THF (100 mL) at 0° C. was added sodium hydride (1.1 gof 60% in oil), followed by addition of allyl bromide (2.3 mL) andtetrabutyl ammonium iodide (1.35 g). The resulting mixture was thenheated to reflux for 5 h. The reaction was carefully quenched with NH₄Cl(aq), extracted with EtOAc, and dried over Na₂SO₄. After concentration,the resulting crude material was filtered through a plug of silica geland rinsed with 20% CH₂Cl₂/hexanes, then concentrated to yield the titlecompound as a yellow oil.

Example 29 2-Trifluoromethyl-2,5-dihydro-furan-2-carboxylic acid ethylester

To a solution of 2-allyloxy-2-trifluoromethyl-but-3-enoic acid ethylester (2.15 g, see above) in CH₂Cl₂ (100 mL) at room temperature wasadded Grubbs catalyst 2^(nd) generation (Aldrich) (67 mg). The resultingmixture was stirred for 18 h at room temperature. The reaction mixturewas then filtered through a plug of Celite® and silica gel, rinsed withEtOAc and then concentrated to yield the title compound as a yellow oil.

Example 305,6-Dichloro-2-(2-trifluoromethyl-2,5-dihydro-furan-2-yl)-1H-benzoimidazole(#45)

To 4,5-dichloro-1,2-diamine (1.56 g) in toluene (10 mL) at 0° C. wasadded neat diethyl aluminum chloride (0.55 mL) and the reaction mixtureallowed to warm to room temperature, then stirred for 1 hr. To theresulting purple-colored slurry, at 0° C., was added2-trifluoromethyl-2,5-dihydro-furan-2-carboxylic acid ethyl ester (464mg). The resulting mixture was stirred at room temperature for 1 hour,then heated to 110° C. for 20 hours. The reaction mixture was quenchedwith 6N HCl, diluted with EtOAc, and washed with 6 N HCl. The organicextracts were dried over Na₂SO₄, filtered, and concentrated to yield aresidue. The residue was purified by flash chromatography with Biotage40s+ column and elution with 10%-40% EtOAc/hexanes to yield an orangegum. The orange gum was dissolved in a minimal amount of CH₂Cl₂ andtriturated with hexanes to yield the title compound as a white powder.

¹H NMR (300 MHz, d₆-DMSO): δ 13.14 (s, 1H), 7.98 (br, 1H), 7.72 (br,1H), 6.62 (d, 1H, J=6.2 Hz), 6.26 (d, 1H, J=6.1 Hz), 4.98 (s, 2H)

MS (M+1)=323.0

Example 315,6-Dichloro-2-(2-trifluoromethyl-tetrahydro-furan-2-yl)-1H-benzoimidazole(#46)

To5,6-dichloro-2-(2-trifluoromethyl-2,5-dihydro-furan-2-yl)-1H-benzimidazole(95 mg) in methanol (5 mL) was added Rhodium on alumina (32 mg). Theresulting mixture was stirred at room temperature under a H₂ atmospherevia balloon for 5 hours. The reaction mixture was then filtered througha pad of Celite®, rinsed with Et₂O, and concentrated to yield the titlecompound as a tan solid.

¹H NMR (300 MHz, d₆-DMSO): δ 13.12 (br, 1H), 7.92 (br, 1H), 7.74 (br,1H), 4.09-4.14 (m, 2H), 2.75-2.84 (m, 1H), 2.54-2.61 (m, 1H), 2.07-2.13(m, 1H), 1.89-1.99 (m, 1H)

Example 322-(5,6-Dichloro-1H-benzoimidazol-2-yl)-3-ethyl-1,1,1-trifluoro-penta-3,4-dien-2-ol(#62)

1-(5,6-Dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (2 g),1-bromo-2-pentyne (1.1 ml) and indium (983 mg) were suspended in THF (15mL) and H₂O (45 mL) and stirred vigorously overnight. The reactionmixture was then diluted with water and ethyl acetate, the layers wereseparated and the aqueous layer was extracted with ethyl acetate. Thecombined extracts were washed with brine and dried over Na₂SO₄ to yielda crude material. The crude material was purified by columnchromatography (SiO₂; 5-30% ethyl acetate/hexanes) to yield the titlecompound as a peach-colored solid.

¹H NMR (300 MHz, d₆-DMSO): δ 12.95 (br, 1H), 7.98 (br, 1H), 7.80 (s,1H), 7.70 (br, 1H), 5.12 (m, 2H), 1.96-2.09 (m, 1H), 1.66-1.79 (m, 1H)

MS (M+H)=351

Example 335,6-Dichloro-2-(2-trifluoromethyl-[1,3]dioxolan-2-yl)-1H-benzimidazole(#47)

1-(5,6-DiChloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (1.14 g;4.02 mmol), 2-chloroethanol (0.83 mL; 12.4 mmol) and potassium carbonate(1.68 g; 12.2 mmol) were dissolved in DMF (18 mL). The reaction mixturewas stirred for 18 hrs at ambient temperature, then diluted with ethylacetate (80 mL), washed with water (50 mL) and brine (2×50 mL). Theextracts were dried over Na₂SO₄, filtered, concentrated to a light brownsolid and the light brown solid purified by column chromatography (SiO₂;30% ethyl acetate/hexanes) to yield the title compound as a tan solid.

¹H NMR (400 MHz, CD₃CN): δ 7.83 (s, 2H), δ 4.29 (m, 4H)

MS calculated for C₁₁H₇Cl₂F₃N₂O₂: 327.09

MS measured: 327, 329 (M+1); 325, 327 (M−H).

Example 345,6-Dichloro-2-(2-trifluoromethyl-[1,3]dioxan-2-yl)-1H-benzimidazole(#51)

1-(5,6-DiChloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (2.13 g;7.51 mmol), 2-chloroethanol (1.90 mL; 22.7 mmol) and potassium carbonate(3.13 g; 22.6 mmol) were dissolved in DMF (14 mL). The reaction mixturewas stirred for 18 hrs at ambient temperature, then diluted with ethylacetate (100 mL), washed with water (80 mL) and brine (2×80 mL). Theextracts were dried over Na₂SO₄, filtered, concentrated to a light brownsolid and the light brown solid purified by column chromatography (SiO₂;20% ethyl acetate/hexanes) to yield the title compound as a light yellowsolid.

¹H NMR (400 MHz, CD₃CN): δ 7.84 (s, 2H), δ 4.14 (m, 2H), δ 3.95 (m, 2H),δ 2.16 (m, 2H)

MS calculated for C₁₂H₉Cl₂F₃N₂O₂: 341.11

MS measured: 341, 343 (M+1); 339, 341 (M−H).

Example 355,6-Dichloro-2-(2-trifluoromethyl-imidazolidin-2-yl)-1H-benzimidazole(#60)

1-(5,6-DiChloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (1.02 g;3.61 mmol), ethylene diamine (0.74 mL; 11.04 mmol) andpara-toluenesulphonic acid monohydrate (0.12 g; 0.603 mmol) weresuspended in toluene (80 mL), then heated to reflux with a Dean-Starktrap for 3 hrs. After 3 hrs, ethylene diamine (0.74 mL; 11.04 mmol) wasadded to the reaction mixture and the reaction mixture was allowed toreflux with the Dean-Stark trap for 18 hrs. The reaction was cooled toroom temperature and concentrated in vacuo to a crude brown residue. Thecrude brown residue was dissolved in ethyl acetate (60 mL), washed withwater (3×50 mL) and brine (50 mL), then dried over Na₂SO₄. The dryingagent was removed by filtration and the filtrate was concentrated invacuo to a crude brown oil, which was purified by column chromatography(SiO₂, 50% ethyl acetate/hexanes) to yield the title compound as a lightorange solid.

¹H NMR (400 MHz, CD₃CN): δ 7.80 (s, 2H), δ 3.32 (br s, 2H), δ 3.06 (m,2H)

MS calculated for C₁₁H₉Cl₂F₃N₄: 325.12

MS measured: 325, 327 (M+1), 323, 325 (M−H).

Example 365,6-Dichloro-1-pyridin-2-ylmethyl-2-(2-trifluoromethyl-[1,3]dioxin-2-yl)-1H-benzimidazole(#48)

5,6-Dichloro-2-(2-trifluoromethyl-[1,3]dioxolan-2-yl)-1H-benzimidazole(0.37 g; 1.1 mmol) was dissolved in DMF (6 mL), treated with 60% NaH inmineral oil 9.14 g; 3.5 mmol) and stirred under a nitrogen atmospherefor 20 minutes. Subsequently, 2-(Bromomethyl)pyridine hydrobromide (0.44g; 1.7 mmol) was added to the reaction mixture and stirred at roomtemperature overnight. The reaction mixture was diluted with ethylacetate (25 mL) and diethyl ether (25 mL), washed with water (30 mL) andbrine (3×30 mL), then dried over Na₂SO₄. The concentrated crude materialwas purified by column chromatography (SiO₂; 50% ethyl acetate/hexanes)to yield the title compound as an off-white solid.

¹H NMR (400 MHz, CD₃CN): δ 8.42 (d, J=4.5 Hz, 1H), δ 7.96 (s, 1H), δ7.70 (d, J=1.6 Hz, 1H), δ 7.67 (s, 1H), δ 7.24 (m, 1H), δ 7.05 (d, J=7.9Hz, 1H), δ 5.67 (s, 2H), δ 4.19 (t, J=7.0 Hz, 2H), δ 3.95 (m, 2H)

MS calculated for C₁₇H₁₂Cl₂F₃N₃O₂: 418.20

MS measured: 418, 420 (M+H).

Example 376-Trifluoromethyl-2-(2-trifluoromethyl-[1,3]dioxolan-2-yl)-1H-benzimidazole-5-carbonitrile(#59)

2-(2,2,2-Trifluoro-acetyl)-6-trifluoromethyl-1H-benzoimidazole-5-carbonitrile(0.50 g; 1.5 mmol), was dissolved in DMF (4 mL), then treated with2-chloroethanol (0.35 mL; 5.2 mmol) and potassium carbonate (0.73 g; 5.3mmol). The reaction mixture was stirred at room temperature overnight.The reaction mixture was then diluted with ethyl acetate (40 mL) anddiethyl ether (40 mL), washed with water (50 mL) and brine (3×30 mL),then dried over Na₂SO₄. The reaction mixture was filtered, concentratedto yield a light brown solid, which was purified by columnchromatography (SiO₂; 100% ethyl acetate) to yield the title compound asa light yellow solid.

¹H NMR (400 MHz, CD₃CN): δ 8.31 (s, 1H), δ 8.17 (s, 1H), δ 4.36 (m, 2H),δ 4.30 (m, 1H)

MS calculated for C₁₃H₇F₆N₃O₂: 351.20

MS measured: 352 (M+1), 350 (M−H).

Example 38 General Procedure for the Alkylation of5,6-Dichloro-2-(2-trifluoromethyl-[1,3]dioxolan-2-yl)-1H-benzimidazole

To a suspension of NaH (1.25 mmol) in dry DMF (5 mL) was added asolution of5,6-dichloro-2-(2-trifluoromethyl-[1,3]dioxolan-2-yl)-1H-benzimidazole(1.0 mmol) in dry DMF (5 mL). After stirring the reaction mixture atroom temperature for 30 min, the suitably substituted electrophile (1-10eq) was added dropwise via syringe. The reaction mixture was stirredovernight at room temperature and then poured onto water (125 mL) withrapid stirring. The resulting precipitate was collected by filtrationand purified by flash chromatography (SiO₂, dcm) to yield the product.

Following the general procedure described above, the following compoundsof the present invention were prepared. After each compound name andstructure is listed the suitably substituted electrophile used in thereaction.

Example 395,6-Dichloro-1-methyl-2-(2-trifluoromethyl-[1,3]dioxolan-2-yl)-1H-benzoimidazole(#52)

Electrophile: Methyl Iodide

Ms (m/z): 341 (MH+)

Example 401-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-5,6-dichloro-2-(2-trifluoromethyl-[1,3]dioxolan-2-yl)-1H-benzoimidazole(#58)

Electrophile: (2-Bromo-ethoxy)-tert-butyl-dimethyl-silane.

Ms (m/z): 485 (MH+)

Example 41[5,6-Dichloro-2-(2-trifluoromethyl-[1,3]dioxolan-2-yl)-benzoimidazol-1-yl]-acetonitrile(#53)

Electrophile: Bromoacetonitrile

Ms (m/z): 366 (MH+)

Example 42[5,6-Dichloro-2-(2-trifluoromethyl-[1,3]dioxolan-2-yl)-benzoimidazol-1-yl]-aceticacid methyl ester (#57)

Electrophile: Methyl Iodoacetate

Ms (m/z): 399 (MH+)

Example 435,6-Dichloro-1-ethyl-2-(2-trifluoromethyl-[1,3]dioxolan-2-yl)-1H-benzoimidazole(#56)

Electrophile: Ethyl Iodide

Ms (m/z): 355 (MH+)

Example 441-Allyl-5,6-dichloro-2-(2-trifluoromethyl-[1,3]dioxolan-2-yl)-1H-benzoimidazole(#55)

Electrophile: Allyl Bromide

Ms (m/z): 367 (MH+)

Example 455,6-Dichloro-1-prop-2-ynyl-2-(2-trifluoromethyl-[1,3]dioxolan-2-yl)-1H-benzoimidazole(#54)

Electrophile: Propargyl Bromide

Ms (m/z): 365 (MH+)

Example 465,6-Dichloro-2-(2-trifluoromethyl-oxazolidin-2-yl)-1H-benzimidazole(#61)

1-(5,6-DiChloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (594mg), 2-bromoethylamine-hydrobromide (860 mg) and potassium carbonate(871 mg) were dissolved in DMF (5 mL). The reaction mixture was stirredfor 18 hrs at ambient temperature, then diluted with ethyl acetate (50mL), washed with water (50 mL) and brine (2×20 mL). The extracts weredried over Na₂SO₄, filtered, concentrated, and purified by columnchromatography (SiO₂; 40% ethyl acetate/hexanes) to yield the titlecompound as a yellow solid.

¹H NMR (400 MHz, d₆DMSO): δ 13.19 (s, 1H), 8.01 (br, 1H), 7.72 (br, 1H),8.01 (br, 1H), 4.50-4.54 (m, 1H), 4.17-4.21 (m, 1H), 3.75-3.81 (m, 1H),3.39-3.41 (m, 1H), 3.03-3.08 (m, 1H)

MS calculated for C₁₁H₈Cl₂F₃N₃O: 325.00, measured as: 326 (M+1).

Example 47[2-(5,6-Dichloro-1H-benzoimidazol-2-yl)-2-trifluoromethyl-[1,3]dioxolan-4-yl]-methanol(#49)

1-(5,6-DiChloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (503mg), 3-chloro-1,2-propan-diol (393 mg) and potassium carbonate (491 mg)were dissolved in DMF (5 mL). The reaction mixture was stirred for 18hrs at ambient temperature, then diluted with ethyl acetate (50 mL),washed with water (50 mL) and brine (2×20 mL). The extracts were driedover Na₂SO₄, filtered, concentrated, and purified by columnchromatography (SiO₂; 40% ethyl acetate/hexanes), followed by washingsolid with CH₂Cl₂/hexanes to yield the title compound as an off-whitesolid.

¹H NMR (300 MHz, d₆DMSO): δ 13.06 (br, 1H), 7.92 (br, 2H), 5.13 (br,1H), 4.59-4.66 (m, 1H), 4.46 (apparent t, 1H, J=7.7 Hz), 4.10 (apparentt, 1H, J=7.3 Hz), 3.52-3.63 (m, 2H)

MS calculated for C₁₂H₉Cl₂F₃N₂O₃: 355.99

Measured: 357 (M+1).

Example 485,6-Dichloro-2-(4-chloromethyl-2-trifluoromethyl-[1,3]dioxolan-2-yl)-1H-benzimidazole(#50)

1-(5,6-Dichloro-1H-benzimidazol-2-yl)-2,2,2-trifluoro-ethanone (611 mg),1,3-dichloro-2-propanyl (557 mg) and potassium carbonate (597 mg) weredissolved in DMF (5 mL). The reaction mixture was stirred for 18 hrs atambient temperature, then diluted with ethyl acetate (50 mL), washedwith water (50 mL) and brine (2×20 mL). The extracts were dried overNa₂SO₄, filtered, concentrated and purified by column chromatography(SiO2; 40% ethyl acetate/hexanes), followed by washing the solid withCH₂Cl₂/hexanes to yield the title compound as an off-white solid.

¹H NMR (300 MHz, d₆DMSO): δ 13.40 (br, 1H0, 8.05 (br, 1H), 4.72-4.78 (m,1H), 4.41-4.46 (m, 1H), 4.09-4.14 (m, 1H), 3.97 (dd, 1H, J=11.8, 4.4Hz), 3.86 (dd, 1H, J=11.0, 6.2 Hz)

MS Calculated for C₁₂H₈Cl₃F₃N₂)₂: 373.96

Measured as 375 (M+1)

Example 492-(5,6-Dichloro-1-methyl-1H-benzoimidazol-2-yl)-1,1,1-trifluoro-pent-4-yn-2-ol(#35)

To a solution of Compound #2 prepared as in Example 4 above, (323 mg, 1mmol) in dry DMF was added sodium hydride (60 mg, 1.5 mmol, 60% inmineral oil). The resulting mixture was then stirred at room temperaturefor 30 mins, cooled to 0° C. and treated with iodomethane (63 μL, 1mmol). After stirring for four hours, TLC indicated consumption ofstarting material. Water was added and the product extracted into ethylacetate. The organic layer was washed with 15% LiCl and then brine.After drying (MgSO₄), the solvent was removed in vacuo to yield thetitle compound as a solid.

MS (m/z): 338 (M+H)

(+)-Enantiomer of2-(5,6-Dichloro-1-methyl-1H-benzoimidazol-2-yl)-1,1,1-trifluoro-pent-4-yn-2-ol(#36) and (−)-Enantiomer of2-(5,6-Dichloro-1-methyl-1H-benzoimidazol-2-yl)-1,1,1-trifluoro-pent-4-yn-2-ol(#37)

Compounds #36 was similarly prepared according to the proceduredescribed above, starting with the (+)-enantiomer, Compound #31,prepared as in Example 4 above.

Compounds #37 was similarly prepared according to the proceduredescribed in Example 49 above, starting from (−)-enantiomer, Compound#32, prepared as in Example 4 above.

Example 50 Ventral Prostate and Levator Ani Weight In Vivo Assay

Immature Rats

Immature (approximately 50 g) castrated male Sprague Dawley rats(Charles River) were treated once daily for five days with test compound(usually given orally at 40 mg/kg in a volume of 0.3 mL, in 30%cyclodextrin or 0.5% methylcellulose vehicle) and with testosteronepropionate (given subcutaneously by injection at the nape of the neck at2 mg/kg, in a volume of 0.1 mL in sesame oil). On the sixth day, therats were euthanized by asphyxiation in carbon dioxide. Ventralprostates and levator ani were removed and their wet weights determined.Test compound activity was determined as the percent inhibition oftestosterone-enhanced tissue weights, with a vehicle-treated controlgroup set to zero percent and a testosterone alone-treated control groupset to 100%.

Mature Rats

Mature (150- to 200-g) castrated male Sprague Dawley rats (CharlesRiver) are similarly tested according to the procedure described above.The rats were dosed for two weeks, with 0.4 mg/kg testosteronepropionate used as the positive control.

Representative compounds of the present invention were tested accordingto the procedure described above, with results as listed in Table 3below. For effect on prostate—i.e. an antagonist—a test compound islisted as “active” in the Table below if the non weight adjustedprostate weight was ≦40 mg or the % Inhibition prostate weight, bodyweight adjusted was ≧40% @ 2 mg/day dosage. For effect on levatorani—i.e. an agonist—a test compound is listed as “active” in the Tablebelow if the non weight adjusted levator ani weight was ≧40 mg or the %Stimulation levator ani weight, body weight adjusted was ≧40% at 2mg/day dosage.

Note that while certain of the compounds listed in Table 3 may or maynot have shown an effect on prostate and/or levator ani weight, they arelisted herein as “inactive” as they did not meet the specified criteriadefined above.

TABLE 3 ID No. Prostate antagonist L.A. agonist 1 active inactive 2active active 3 active active 4 active active 6 active inactive 7inactive active 8 active inactive 9 active inactive 10 active inactive13 active inactive 14 active inactive 15 active active 16 activeinactive 17 active inactive 23 active inactive 24 active inactive 25active inactive 26 active inactive 27 inactive inactive 28 activeinactive 31 active active 32 active inactive 34 inactive inactive 35inactive 36 inactive inactive 37 inactive active 38 active active 39active inactive 40 active 41 active inactive 42 active inactive 43inactive active 44 inactive inactive 45 inactive active 46 active active47 active 48 inactive inactive 49 active inactive 50 active 51 activeinactive 52 inactive 53 active 54 active 55 active 56 active 57 inactive59 active inactive 60 active 61 active inactive 62 active

Example 51

As a specific embodiment of an oral composition, 50 mg of Compound #43prepared as described in Example 26 above is formulated with sufficientfinely divided lactose to provide a total amount of 580 to 590 mg tofill a size O hard gel capsule.

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations and/or modifications as come withinthe scope of the following claims and their equivalents.

We claim:
 1. A method of treating a condition selected from the groupconsisting of prostate carcinoma, benign prostatic hyperplasia (BPH),hirsutism, alopecia, anorexia nervosa, breast cancer, acne, cachexia,diminished libido, male contraception, and male performance, comprisingadministering to subject in need thereof a therapeutically effectiveamount of a compound of formula (I)

wherein R¹ is selected from the group consisting of—(CH₂)—(C₂₋₄alkenyl), —(CH₂)—(C₂₋₄alkynyl), fluorinated lower alkyl,-(lower alkyl)-CN, —(CH₂)-heteroaryl, —(CH₂)-aryl, —SO₂-(lower alkyl),—SO₂-(phenyl), —SO₂-(tolyl), —(CH₂)-(fluorinated lower alkyl), -(loweralkyl)-C(O)—O-(lower alkyl), -(lower alkyl)-O-(lower alkyl), -(loweralkyl)-S(O)₀₋₂-(lower alkyl) and -(lower alkyl)-O—Si(CH₃)₂(t-butyl); R²and R³ are each independently selected from the group consisting ofhalogen, hydroxy, carboxy, lower alkyl, halogen substituted lower alkyl,lower alkoxy, halogen substituted lower alkoxy, cyano, nitro, amino,lower alkylamino, di(lower alkyl)amino, —C(O)-(lower alkyl),—C(O)-(lower alkoxy), —C(O)—NR^(A)R^(B), —S(O)₀₋₂-(lower alkyl),—SO₂—NR^(A)R^(B), —N(R^(A))—C(O)-(lower alkyl) and—N(R^(A))—C(O)-(halogen substituted lower alkyl); wherein each R^(A) andR^(B) is independently selected from hydrogen or lower alkyl; R⁴ isselected from the group consisting of alkenyl, alkynyl, aryl,—(C₂₋₄alkyl)-aryl, heteroaryl and —(C₂₋₄alkyl)-heteroaryl; wherein thealkenyl or alkynyl is optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, hydroxy, carboxy, cyano, nitro, NR^(E)R^(F), NR^(E)—C(O)-loweralkyl and phenyl; wherein R^(E) and R^(F) are each independentlyselected from hydrogen or lower alkyl; and wherein the phenyl isoptionally substituted with one to four substituents independentlyselected from the group consisting of halogen, lower alkyl, loweralkoxy, hydroxy, carboxy, cyano, nitro, amino, (lower alkyl)amino anddi(lower alkyl)amino; wherein the aryl or heteroaryl, whether alone oras part of a substituent group is optionally substituted with one ormore substituents independently selected from the group consisting ofhalogen, hydroxy, carboxy, lower alkyl, lower alkoxy, fluorinated loweralkyl, fluorinated lower alkoxy, phenoxy, cyano, nitro, NR^(C)R^(D) and-(lower alkyl)-NR^(B)R^(C), —C(O)-(lower alkyl), —C(O)-(lower alkoxy),—C(O)—NR^(C)R^(D), —N(R^(C))—C(O)-(lower alkyl), —N(R^(C))—C(O)-(halogensubstituted lower alkyl), —S(O)₀₋₂-(lower alkyl) and —SO₂—NR^(C)R^(D);wherein each R^(C) and R^(D) is independently selected from hydrogen orlower alkyl; R⁵ is OR⁶; wherein R⁶ is selected from the group consistingof hydrogen, lower alkyl and —C(O)-(lower alkyl); alternatively, R⁴ andR⁵ are taken together with the atom to which they are bound to form aring structure selected from the group consisting of 2-pyrrolidinyl,2-tetrahydro-furanyl, 2-(2,5-dihydro-1H-pyrrolyl),2-(2,5-dihydro-furanyl), 2-imidazolidinyl, 2-oxazolidinyl,2-[1,3]dioxolanyl, 2-piperidinyl, 6-(1,2,3,6-tetrahydro-pyridinyl),2-(1,2,3,6-tetrahydro-pyridinyl), 2-tetrahydropyranyl,6-(3,6-dihydro-2H-pyranyl), 2-(3,6-dihydro-2H-pyranyl),2-(hexahydro-pyrimidinyl), 2-[1,3]oxazinanyl and 2-[1,3]dioxanyl;wherein the ring structure is optionally substituted with one or moresubstituents independently selected from the group consisting of loweralkyl, -(lower alkyl)-OH and -(lower alkyl)-(halogen); andpharmaceutically acceptable salts thereof.
 2. The method of claim 1,comprising treating the subject with a pharmaceutical compositioncomprising a pharmaceutically acceptable carrier and the compound offormula (I).
 3. The method of claim 1, wherein R¹ is selected from thegroup consisting of -(lower alkyl)-CN, —(CH₂)—(C₂₋₄alkenyl),—(CH₂)—(C₂₋₄alkynyl), fluorinated lower alkyl, —(CH₂)-heteroaryl,—(CH₂)-aryl, —(CH₂)-(fluorinated lower alkyl), -(loweralkyl)-C(O)—O-(lower alkyl), -(lower alkyl)-O-(lower alkyl), and -(loweralkyl)-O—Si(CH₃)₂(t-butyl); R² and R³ are each independently selectedfrom the group consisting of halogen, hydroxy, carboxy, lower alkyl,halogen substituted lower alkyl, cyano, nitro, amino, lower alkylamino,di(lower alkyl)amino, —C(O)-(lower alkyl), —C(O)-(lower alkoxy),—C(O)—NR^(A)R^(B), —N(R^(A))—C(O)-(lower alkyl) and—N(R^(A))—C(O)-(halogen substituted lower alkyl); wherein each R^(A) andR^(B) is independently selected from hydrogen, methyl or ethyl; R⁴ isselected from the group consisting of alkenyl, alkynyl, aryl,—(C₂₋₄alkyl)-aryl, heteroaryl and —(C₂₋₄alkyl)-heteroaryl; wherein thealkenyl or alkynyl is optionally substituted with one substituentselected from the group consisting of halogen, hydroxy, carboxy, cyano,nitro, NR^(E)R^(F), NR^(E)—C(O)-lower alkyl and phenyl; wherein R^(E)and R^(F) are each independently selected from hydrogen or lower alkyl;and wherein the phenyl is optionally substituted with one to twosubstituents independently selected from the group consisting ofhalogen, lower alkyl, lower alkoxy, hydroxy, carboxy, cyano, nitro,amino, (lower alkyl)amino and di(lower alkyl)amino; wherein the aryl orheteroaryl, whether alone or as part of a substituent group isoptionally substituted with one to two substituents selected from thegroup consisting of halogen, hydroxy, carboxy, lower alkyl, loweralkoxy, fluorinated lower alkyl, fluorinated lower alkoxy, phenoxy,cyano, nitro, NR^(C)R^(D), -(lower alkyl)-NR^(B)R^(C), —C(O)-(loweralkyl) and —C(O)-(lower alkoxy); and wherein each R^(C) and R^(D) isindependently selected from hydrogen or lower alkyl, R⁵ is OR⁶; whereinR⁶ is selected from the group consisting of hydrogen, methyl, ethyl,—C(O)-methyl and —C(O)-ethyl; alternatively, R⁴ and R⁵ are takentogether with the atom to which they are bound to form a ring structureselected from the group consisting of 2-pyrrolidinyl,2-tetrahydro-furanyl, 2-(2,5-dihydro-1H-pyrrolyl),2-(2,5-dihydro-furanyl), 2-imidazolidinyl, 2-oxazolidinyl,2-[1,3]dioxolanyl, 2-piperidinyl, 6-(1,2,3,6-tetrahydro-pyridinyl),2-(1,2,3,6-tetrahydro-pyridinyl), 2-tetrahydropyranyl,6-(3,6-dihydro-2H-pyranyl), 2-(3,6-dihydro-2H-pyranyl),2-(hexahydro-pyrimidinyl), 2-[1,3]oxazinanyl and 2-[1,3]dioxanyl;wherein the ring structure is optionally substituted with one or moresubstituents independently selected from the group consisting ofC₁₋₂alkyl, —(C₁₋₂alkyl)-OH and —(C₁₋₂alkyl)-halogen; or apharmaceutically acceptable salt thereof.
 4. The method of claim 3,wherein R¹ is selected from the group consisting of -(lower alkyl)-CN,—(CH₂)-heteroaryl, —(CH₂)—(C₂₋₄alkenyl), —(CH₂)—(C₂₋₄alkynyl), -(loweralkyl)-C(O)O-(lower alkyl) and -(lower alkyl)-O—Si(CH₃)₂(t-butyl); R²and R³ are each independently selected from the group consisting ofhalogen, cyano and halogen substituted lower alkyl; R⁴ is selected fromthe group consisting of alkenyl, alkynyl and aryl; wherein the alkenyl,or alkynyl is optionally substituted with a substituent selected fromthe group consisting of hydroxy, carboxy and phenyl; R⁵ is OH;alternatively, R⁴ and R⁵ are taken together with the atom to which theyare bound to form a ring structure selected from the group consisting of2-(2,5-dihydro-furanyl), 2-tetrahydrofuranyl, 2-[1,3]-dioxolanyl,2-[1,3]dioxanyl, 2-imidazolidinyl, and 2-oxazolidinyl; wherein the ringstructure is optionally substituted with one to two substituentsindependently selected from the group consisting of methyl, ethyl,hydroxymethyl, hydroxyethyl, and —(C₁₋₂alkyl)-halogen; or apharmaceutically acceptable salt thereof.
 5. The method of claim 4,wherein R¹ is selected from the group consisting of cyano-methyl-,2-pyridyl-methyl-, allyl, 1-propyn-3-yl, methoxy-carbonyl-methyl- andt-butyl-dimethyl-silyloxy-ethyl-; R² is selected from the groupconsisting of chloro and trifluoromethyl; R³ is selected from the groupconsisting of chloro and cyano; R⁴ is selected from the group consistingof vinyl, (+)-vinyl, (−)-vinyl, allyl, (+)-allyl, (−)-allyl,2-methyl-allyl, 2-propen-3-yl, Z-2-propen-3-yl, E-2-propen-3-yl,3-methyl-1-propen-3-yl, 2-carboxy-1-propen-3-yl, 3-phenyl-1-propen-3-yl,3,3-dimethyl-1-propen-3-yl, 2,3-dimethyl-2-propen-3-yl,2-methyl-2-propen-3-yl), isopropenyl, propa-1,2-dien-3-yl,3-methyl-propa-1,2-dien-3-yl, 3-ethyl-propa-1,2-dien-3-yl),1-buten-4-yl, 1-propyn-3-yl, (+)-1-propyn-3-yl, (−)-1-propyn-3-yl,2-propyn-3-yl, 1-hydroxy-2-propyn-3-yl, 1-phenyl-1-propyn-3-yl,2-butyn-4-yl and phenyl; R⁵ is OH; alternatively, R⁴ and R⁵ are takentogether with the atom to which they are bound to form a ring structureselected from the group consisting of 2,5-dihydro-furanyl),2-tetrahydrofuranyl, 2-[1,3]-dioxolanyl,2-(4-hydroxymethyl-[1,3]dioxalanyl), 2-(4-chloromethyl-[1,3]dioxalanyl,2-[1,3]dioxanyl, 2-imidazolidinyl, and 2-oxazolidinyl; or apharmaceutically acceptable salt thereof.
 6. The method of claim 5,wherein R¹ is selected from the group consisting of cyano-methyl-, allyland 1-propyn-3-yl; R² is selected from the group consisting of chloroand trifluoromethyl; R³ is selected from the group consisting of chloroand cyano; R⁴ is selected from the group consisting of vinyl, allyl,(+)-allyl, (−)-allyl, 2-methyl-allyl, 2-propen-3-yl, Z-2-propen-3-yl,E-2-propen-3-yl, 3-methyl-1-propen-3-yl, 3-phenyl-1-propen-3-yl,3,3-dimethyl-1-propen-3-yl, 2,3-dimethyl-2-propen-3-yl,2-methyl-2-propen-3-yl, isopropenyl, propa-1,2-dien-3-yl,3-methyl-propa-1,2-dien-3-yl, 3-ethyl-propa-1,2-dien-3-yl, 1-buten-4-yl,1-propyn-3-yl, (+)-1-propyn-3-yl, (−)-1-propyn-3-yl, 2-propyn-3-yl andphenyl; R⁵ is OH; alternatively, R⁴ and R⁵ are taken together with theatom to which they are bound to form a ring structure selected from thegroup consisting of 2-tetrahydrofuranyl, 2-[1,3]-dioxolanyl,2-(4-hydroxymethyl-[1,3]dioxalanyl), 2-(4-chloromethyl-[1,3]dioxalanyl,2-[1,3]dioxanyl, 2-imidazolidinyl, and 2-oxazolidinyl; or apharmaceutically acceptable salt thereof.
 7. The method of claim 6,wherein R² is selected from the group consisting of chloro andtrifluoromethyl; R³ is selected from the group consisting of chloro andcyano; R⁴ is selected from the group consisting of vinyl, (+)-vinyl,allyl, Z-2-propen-3-yl, propa-1,2-dien-3-yl, 1-propyn-3-yl,(+)-1-propyn-3-yl and (−)-1-propyn-3-yl; R⁵ is OH; alternatively, R⁴ andR⁵ are taken together with the atom to which they are bound to form aring structure selected from the group consisting of2-(2,5-dihydro-furanyl) and 2-tetrahydrofuranyl; or a pharmaceuticallyacceptable salt thereof.
 8. The method of claim 3, wherein R¹ isselected from the group consisting of -(lower alkyl)-CN,—(CH₂)-heteroaryl, —(CH₂)—(C₂₋₄alkenyl), —(CH₂)—(C₂₋₄alkynyl), -(loweralkyl)-C(O)O-(lower alkyl) and -(lower alkyl)-O—Si(CH₃)₂(t-butyl); R²and R³ are each independently selected from the group consisting ofhalogen and halogen substituted lower alkyl; R⁴ and R⁵ are takentogether with the atom to which they are bound to form a ring structureselected from the group consisting of 2-(2,5-dihydro-furanyl),2-tetrahydrofuranyl, 2-[1,3]-dioxolanyl, 2-[1,3]dioxanyl,2-imidazolidinyl, and 2-oxazolidinyl; wherein the ring structure isoptionally substituted with one to two substituents independentlyselected from the group consisting of hydroxymethyl, hydroxyethyl, and—(C₁₋₂alkyl)-halogen; or a pharmaceutically acceptable salt thereof. 9.The method of claim 8, wherein R¹ is selected from the group consistingof cyano-methyl-, 2-pyridyl-methyl-, allyl, 1-propyn-3-yl,methoxy-carbonyl-methyl- and t-butyl-dimethyl-silyloxy-ethyl-; R² isselected from the group consisting of chloro and trifluoromethyl; R³ ischloro; R⁴ and R⁵ are taken together with the atom to which they arebound to form a ring structure selected from the group consisting of2-(2,5-dihydro-furanyl), 2-tetrahydrofuranyl, 2-[1,3]-dioxolanyl,2-(4-hydroxymethyl-[1,3]dioxalanyl), 2-(4-chloromethyl-[1,3]dioxalanyl,2-[1,3]dioxanyl, 2-imidazolidinyl, and 2-oxazolidinyl; or apharmaceutically acceptable salt thereof.